Amide-substituted heterocyclic compounds for the treatment of conditions related to the modulation of il-12, il-23 and/or ifn-alpha

ABSTRACT

Compounds having the following formula I: or a stereoisomer or pharmaceutically-acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , and R 5  are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/752,414, filed Oct. 30, 2018, the disclosure of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to compounds useful in the modulation of IL-12,IL-23 and/or IFNα by acting on Tyk-2 to cause signal transductioninhibition. Provided herein are amide-substituted heterocycliccompounds, compositions comprising such compounds, and methods of theiruse. The invention further pertains to pharmaceutical compositionscontaining at least one compound according to the invention that areuseful for the treatment of conditions related to the modulation ofIL-12, IL-23 and/or IFNα in a mammal.

BACKGROUND OF THE INVENTION

The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share acommon p40 subunit, are produced by activated antigen-presenting cellsand are critical in the differentiation and proliferation of Th1 andTh17 cells, two effector T cell lineages which play key roles inautoimmunity. IL-23 is composed of the p40 subunit along with a uniquep19 subunit. IL-23, acting through a heterodimeric receptor composed ofIL-23R and IL-12Rβ1, is essential for the survival and expansion of Th17cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F,IL-6 and TNF-α (McGeachy, M. J. et al., “The link between IL-23 and Th17cell-mediated immune pathologies”, Semin. Immunol., 19:372-376 (2007)).These cytokines are critical in mediating the pathobiology of a numberof autoimmune diseases, including rheumatoid arthritis, multiplesclerosis, inflammatory bowel disease, and lupus. IL-12, in addition tothe p40 subunit in common with IL-23, contains a p35 subunit and actsthrough a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2.IL-12 is essential for Th1 cell development and secretion of IFNγ, acytokine which plays a critical role in immunity by stimulating MHCexpression, class switching of B cells to IgG subclasses, and theactivation of macrophages (Gracie, J. A. et al., “Interleukin-12 inducesinterferon-gamma-dependent switching of IgG alloantibody subclass”, Eur.J. Immunol., 26:1217-1221 (1996); Schroder, K. et al.,“Interferon-gamma: an overview of signals, mechanisms and functions”, J.Leukoc. Biol., 75(2):163-189 (2004)).

The importance of the p40-containing cytokines in autoimmunity isdemonstrated by the discovery that mice deficient in either p40, p19, orIL-23R are protected from disease in models of multiple sclerosis,rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis,among others (Kyttaris, V. C. et al., “Cutting edge: IL-23 receptordeficiency prevents the development of lupus nephritis inC57BL/6-lpr/lpr mice”, J. Immunol., 184:4605-4609 (2010); Hong, K. etal., “IL-12, independently of IFN-gamma, plays a crucial role in thepathogenesis of a murine psoriasis like skin disorder”, J. Immunol.,162:7480-7491 (1999); Hue, S. et al., “Interleukin-23 drives innate andT cell-mediated intestinal inflammation”, J. Exp. Med., 203:2473-2483(2006); Cua, D. J. et al., “Interleukin-23 rather than interleukin-12 isthe critical cytokine for autoimmune inflammation of the brain”, Nature,421:744-748 (2003); Murphy, C. A. et al., “Divergent pro- andanti-inflammatory roles for IL-23 and IL-12 in joint autoimmuneinflammation”, J. Exp. Med., 198:1951-1957 (2003)).

In human disease, high expression of p40 and p19 has been measured inpsoriatic lesions, and Th17 cells have been identified in active lesionsin the brain from MS patients and in the gut mucosa of patients withactive Crohn's disease (Lee, E. et al., “Increased expression ofinterleukin 23 p19 and p40 in lesional skin of patients with psoriasisvulgaris”, J. Exp. Med., 199:125-130 (2004); Tzartos, J. S. et al.,“Interleukin-17 production in central nervous system infiltrating Tcells and glial cells is associated with active disease in multiplesclerosis”, Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of p19,p40, and p35 in active SLE patients were also shown to be significantlyhigher compared with those in inactive SLE patients (Huang, X. et al.,“Dysregulated expression of interleukin-23 and interleukin-12 subunitsin systemic lupus erythematosus patients”, Mod. Rheumatol., 17:220-223(2007)), and T cells from lupus patients have a predominant Th1phenotype (Tucci, M. et al., “Overexpression of interleukin-12 and Thelper 1 predominance in lupus nephritis”, Clin. Exp. Immunol.,154:247-254 (2008)).

Moreover, genome-wide association studies have identified a number ofloci associated with chronic inflammatory and autoimmune diseases thatencode factors that function in the IL-23 and IL-12 pathways. Thesegenes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2,STAT3, and STAT4 (Lees, C. W. et al., “New IBD genetics: common pathwayswith other diseases”, Gut, 60:1739-1753 (2011); Tao, J. H. et al.,“Meta-analysis of TYK2 gene polymorphisms association withsusceptibility to autoimmune and inflammatory diseases”, Mol. Biol.Rep., 38:4663-4672 (2011); Cho, J. H. et al., “Recent insights into thegenetics of inflammatory bowel disease”, Gastroenterology, 140:1704-1712(2011)).

Indeed, anti-p40 treatment, which inhibits both IL-12 and IL-23, as wellas IL-23-specific anti-p19 therapies have been shown to be efficaciousin the treatment of autoimmunity in diseases including psoriasis,Crohn's Disease and psoriatic arthritis (Leonardi, C. L. et al.,“PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, ahuman interleukin-12/23 monoclonal antibody, in patients with psoriasis:76-week results from a randomized, double-blind, placebo-controlledtrial (PHOENIX 1)”, Lancet, 371:1665-1674 (2008); Sandborn, W. J. etal., “Ustekinumab Crohn's Disease Study Group. A randomized trial ofUstekinumab, a human interleukin-12/23 monoclonal antibody, in patientswith moderate-to-severe Crohn's disease”, Gastroenterology,135:1130-1141 (2008); Gottlieb, A. et al., “Ustekinumab, a humaninterleukin 12/23 monoclonal antibody, for psoriatic arthritis:randomized, double-blind, placebo-controlled, crossover trial”, Lancet,373:633-640 (2009)). Therefore, agents which inhibit the action of IL-12and IL-23 may be expected to have therapeutic benefit in humanautoimmune disorders.

The Type I group of interferons (IFNs), which include the IFNα membersas well as IFNβ, IFNε, IFNκ and IFNω, act through a heterodimer IFNα/βreceptor (IFNAR). Type I IFNs have multiple effects in both the innateand adaptive immune systems including activation of both the cellularand humoral immune responses as well as enhancing the expression andrelease of autoantigens (Hall, J. C. et al., “Type I interferons:crucial participants in disease amplification in autoimmunity”, Nat.Rev. Rheumatol., 6:40-49 (2010)).

In patients with systemic lupus erythematosus (SLE), a potentially fatalautoimmune disease, increased serum levels of interferon (IFN)α (a typeI interferon) or increased expression of type I IFN-regulated genes (aso-called IFNα signature) in peripheral blood mononuclear cells and inaffected organs has been demonstrated in a majority of patients(Bennett, L. et al., “Interferon and granulopoiesis signatures insystemic lupus erythematosus blood”, J. Exp. Med., 197:711-723 (2003);Peterson, K. S. et al., “Characterization of heterogeneity in themolecular pathogenesis of lupus nephritis from transcriptional profilesof laser-captured glomeruli”, J. Clin. Invest., 113:1722-1733 (2004)),and several studies have shown that serum IFNα levels correlate withboth disease activity and severity (Bengtsson, A. A. et al., “Activationof type I interferon system in systemic lupus erythematosus correlateswith disease activity but not with antiretroviral antibodies”, Lupus,9:664-671 (2000)). A direct role for IFNα in the pathobiology of lupusis evidenced by the observation that the administration of IFNα topatients with malignant or viral diseases can induce a lupus-likesyndrome. Moreover, the deletion of the IFNAR in lupus-prone miceprovides high protection from autoimmunity, disease severity andmortality (Santiago-Raber, M. L. et al., “Type-I interferon receptordeficiency reduces lupus-like disease in NZB mice”, J. Exp. Med.,197:777-788 (2003)), and genome-wide association studies have identifiedloci associated with lupus that encode factors that function in the typeI interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y.et al., “Genetic susceptibility to systemic lupus erythematosus in thegenomic era”, Nat. Rev. Rheumatol., 6:683-692 (2010); Sandling, J. K. etal., “A candidate gene study of the type I interferon pathway implicatesIKBKE and IL8 as risk loci for SLE”, Eur. J. Hum. Genet., 19:479-484(2011)). In addition to lupus, there is evidence that aberrantactivation of type I interferon-mediated pathways are important in thepathobiology of other autoimmune diseases such as Sjögren's syndrome andscleroderma (Båve, U. et al., “Activation of the type I interferonsystem in primary Sjögren's syndrome: a possible etiopathogenicmechanism”, Arthritis Rheum., 52:1185-1195 (2005); Kim, D. et al.,“Induction of interferon-alpha by scleroderma sera containingautoantibodies to topoisomerase I: association of higherinterferon-alpha activity with lung fibrosis”, Arthritis Rheum.,58:2163-2173 (2008)). Therefore, agents which inhibit the action of typeI interferon responses may be expected to have therapeutic benefit inhuman autoimmune disorders.

Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family ofnonreceptor tyrosine kinases and has been shown to be critical inregulating the signal transduction cascade downstream of receptors forIL-12, IL-23 and type I interferons in both mice (Ishizaki, M. et al.,“Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17Axes In vivo”, J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. etal., “TYK2 kinase activity is required for functional type I interferonresponses in vivo”, PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y.et al., “Human tyrosine kinase 2 deficiency reveals its requisite rolesin multiple cytokine signals involved in innate and acquired immunity”,Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-inducedphosphorylation of members of the STAT family of transcription factors,an essential signal that leads to the dimerization of STAT proteins andthe transcription of STAT-dependent pro-inflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis,psoriasis and multiple sclerosis, demonstrating the importance ofTyk2-mediated signaling in autoimmunity and related disorders (Ishizaki,M. et al., “Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 andIL-23/Th17 Axes In vivo”, J. Immunol., 187:181-189 (2011); Oyamada, A.et al., “Tyrosine kinase 2 plays critical roles in the pathogenic CD4 Tcell responses for the development of experimental autoimmuneencephalomyelitis”, J. Immunol., 183:7539-7546 (2009)).

In humans, individuals expressing an inactive variant of Tyk2 areprotected from multiple sclerosis and possibly other autoimmunedisorders (Couturier, N. et al., “Tyrosine kinase 2 variant influences Tlymphocyte polarization and multiple sclerosis susceptibility”, Brain,134:693-703 (2011)). Genome-wide association studies have shown othervariants of Tyk2 to be associated with autoimmune disorders such asCrohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoidarthritis, further demonstrating the importance of Tyk2 in autoimmunity(Ellinghaus, D. et al., “Combined Analysis of Genome-wide AssociationStudies for Crohn Disease and Psoriasis Identifies Seven SharedSusceptibility Loci”, Am. J. Hum. Genet., 90:636-647 (2012); Graham, D.et al., “Association of polymorphisms across the tyrosine kinase gene,TYK2 in UK SLE families”, Rheumatology (Oxford), 46:927-930 (2007);Eyre, S. et al., “High-density genetic mapping identifies newsusceptibility loci for rheumatoid arthritis”, Nat. Genet., 44:1336-1340(2012)).

In view of the conditions that may benefit by treatment involving themodulation of cytokines and/or interferons, new compounds capable ofmodulating cytokines and/or interferons, such as IL-12, IL-23 and/orIFNα, and methods of using these compounds may provide substantialtherapeutic benefits to a wide variety of patients in need thereof.

SUMMARY OF THE INVENTION

The invention is directed to compounds of Formula I, infra, that whichare useful as modulators of IL-12, IL-23 and/or IFNα by inhibitingTyk2-mediated signal transduction.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention.

The present invention also provides a method for the modulation ofIL-12, IL-23 and/or IFNα by inhibiting Tyk-2-mediated signaltransduction comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention.

A preferred embodiment is a method for treating inflammatory andautoimmune diseases or diseases. For the purposes of this invention, aninflammatory and autoimmune disease or disorder includes any diseasehaving an inflammatory or autoimmune component.

The present invention also provides the use of the compounds of thepresent invention for the manufacture of a medicament for the treatmentof cancers.

The present invention also provides the compounds of the presentinvention for use in therapy.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

In a first aspect of the present invention, there is provided a compoundof formula (I)

wherein

X is N or CH;

R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle;

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a second aspect of the present invention, there is provided acompound of the formula

wherein

X is N or CH;

R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H or C₁₋₃ alkyl;

R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle;

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a third aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H or C₁₋₃ alkyl;

R⁵ is C₁₋₄ alkyl or C₁₋₄ alkoxy;

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 4th aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H or C₁₋₃ alkyl;

R⁵ is C₁₋₄ alkyl or C₁₋₄ alkoxy,

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 5th aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁵ is C₁₋₄ alkyl or C₁₋₄ alkoxy,

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 6th aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 7th aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁶ is a triazole, oxadiazole, thiazole, oxazole or pyrazole substitutedwith 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In an 8th aspect of the present invention, there is provided a compoundof the formula

wherein

X is N or CH;

R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, pyridine, pyridazine,pyrazole, triazole or piperazine, all of which, except the H group, maybe substituted with 0-3 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁶ is a triazole, oxadiazole, thiazole, oxazole or pyrazole substitutedwith 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 9th aspect of the present invention, there is provided a compoundof the formula

wherein

R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle;

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 10th aspect of the present invention, there is provided a compoundof the formula

wherein

R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, pyridine, pyridazine,pyrazole, triazole or piperazine, all of which, except the H group, maybe substituted with 0-3 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁶ is a triazole, oxadiazole, thiazole, oxazole or pyrazole substitutedwith 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In an 11th aspect of the present invention, there is provided a compoundof the formula

wherein

R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R³ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;

R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r-)phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle;

R^(5a) is independently at each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃alkyl or (CH₂)_(r)-phenyl;

R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In a 12th aspect of the present invention, there is provided a compoundof the formula

wherein

R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, pyridine, pyridazine,pyrazole, triazole or piperazine, all of which, except the H group, maybe substituted with 0-3 R^(2a);

R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁴ is H or C₁₋₃ alkyl;

R⁶ is a triazole, oxadiazole, thiazole, oxazole or pyrazole substitutedwith 0-3 R^(6a);

R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a);

R⁷ is H, halogen or C₁₋₃ alkyl;

R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d);

R^(a) at each occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),—S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(f);

R^(b) is H, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d);

R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f);

R^(d) is independently at each occurrence, hydrogen, F, Cl, Br, OCF₃,CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenyl substituted with 0-3R^(f);

R^(e) is independently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);

R^(f) is independently at each occurrence, hydrogen, halo, CN, NH₂, OH,C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 memberedheterocycle;

p is 0, 1, or 2;

r is 0, 1, 2, 3, 4 or 5;

or a stereoisomer or pharmaceutically acceptable salt thereof.

In another aspect, there is provided a compound selected from theexemplified examples within the scope of the first aspect, or apharmaceutically acceptable salt or stereoisomer thereof.

In another aspect, there is provided a compound selected from any subsetlist of compounds within the scope of any of the above aspects.

In another aspect, there is provided a compound (IUPAC namingconvention) selected from

-   6-cyclopropaneamido-4-{[2-methoxy-3-(5-{1-[(2-methoxyethyl)carbamoyl]propyl}-1,2,4-oxadiazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide,-   6-cyclopropaneamido-4-[(2-methoxy-3-{5-[1-(morpholin-4-yl)-1-oxopentan-2-yl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   6-cyclopropaneamido-4-{[2-methoxy-3-(5-{1-[(2-methoxyethyl)    carbamoyl]butyl}-1,2,4-oxadiazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide,-   tert-butyl    N-[(1R,2R)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}propyl]carbamate,-   6-cyclopropaneamido-4-[(3-{3-[(1R,2R)-1-acetamido-2-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   methyl    N-[(1R,2R)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}-2-hydroxypropyl]carbamate,-   6-cyclopropaneamido-4-[(3-{3-[(1R,2R)-2-hydroxy-1-propanamidopropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   tert-butyl    N-[(1R)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}ethyl]carbamate,-   6-cyclopropaneamido-4-[(3-{3-[(1R)-2-hydroxy-1-propanamidoethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   6-cyclopropaneamido-4-[(3-{3-[(1R)-1-acetamido-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   (2R)-2-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}-2-acetamidoethyl    acetate,-   6-cyclopropaneamido-4-[(3-{3-[(1R)-2-hydroxy-1-(2-methoxyacetamido)ethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-1-acetamido-2-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-2-hydroxy-1-(2-methoxyacetamido)propyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   tert-butyl    N-[(1S,2S)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}propyl]carbamate,-   6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-2-hydroxy-1-propanamidopropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,-   tert-butyl    N-[(1S)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}ethyl]carbamate,    or-   6-cyclopropaneamido-4-[(3-{3-[(1S)-1-acetamido-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,

or a pharmaceutically acceptable salt thereof.

In another embodiment, there is provided a pharmaceutical compositioncomprising one or more compounds of formula I and a pharmaceuticallyacceptable carrier or diluent.

The present invention is also directed to pharmaceutical compositionsuseful in treating diseases associated with the modulation of IL-12,IL-23 and/or IFNα by acting on Tyk-2 to cause signal transductioninhibition, comprising compounds of formula I, orpharmaceutically-acceptable salts thereof, andpharmaceutically-acceptable carriers or diluents.

The invention further relates to methods of treating diseases associatedwith the modulation of IL-12, IL-23, and/or IFNα, comprisingadministering to a patient in need of such treatment atherapeutically-effective amount of a compound according to formula TThe present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides a method for treating proliferative,metabolic, allergic, autoimmune and inflammatory diseases (or use of thecompounds of the present invention for the manufacture of a medicamentfor the treatment of these diseases), comprising administering to a hostin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention.

The present invention also provides a method of treating an inflammatoryor autoimmune disease (or use of the compounds of the present inventionfor the manufacture of a medicament for the treatment of these diseases)comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I.

The present invention also provides a method for treating a disease (oruse of the compounds of the present invention for the manufacture of amedicament for the treatment of these diseases), comprisingadministering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thedisease is rheumatoid arthritis, multiple sclerosis, systemic lupuserythematosus (SLE), lupus nephritis, cutaneous lupus, inflammatorybowel disease, psoriasis, Crohn's Disease, psoriatic arthritis,Sjögren's syndrome, systemic scleroderma, ulcerative colitis, Graves'disease, discoid lupus erythematosus, adult onset Stills, systemic onsetjuvenile idiopathic arthritis, gout, gouty arthritis, type 1 diabetes,insulin dependent diabetes mellitus, sepsis, septic shock, Shigellosis,pancreatitis (acute or chronic), glomerulonephritis, autoimmunegastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, myasthenia gravis,pancreatitis (acute or chronic), ankylosing spondylitis, pemphigusvulgaris, Goodpasture's disease, antiphospholipid syndrome, idiopathicthrombocytopenia, ANCA-associated vasculitis, pemphigus, Kawasakidisease, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP),dermatomyositis, polymyositis, uveitis, Guillain-Barre syndrome,autoimmune pulmonary inflammation, autoimmune thyroiditis, autoimmuneinflammatory eye disease, and chronic demyelinating polyneuropathy.

The present invention also provides a method of treating an inflammatoryor autoimmune disease (or use of the compounds of the present inventionfor the manufacture of a medicament for the treatment of said diseases),comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thedisease is selected from systemic lupus erythematosus (SLE), lupusnephritis, cutaneous lupus, Crohn's Disease, ulcerative colitis, type 1diabetes, psoriasis, rheumatoid arthritis, systemic onset juvenileidiopathic arthritis, ankylosing spondylitis, and multiple sclerosis.

The present invention also provides a method for treating rheumatoidarthritis or the use of the compounds of the present invention for themanufacture of a medicament for the treatment of rheumatoid arthritis,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I.

In addition, the present invention also provides a method of treating acondition (or use of the compounds of the present invention for themanufacture of a medicament for the treatment of these conditions)comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of Formula I, wherein thecondition is selected from acute myelogenous leukemia, chronicmyelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, solid tumors, ocular neovasculization, and infantilehaemangiomas, B cell lymphoma, systemic lupus erythematosus (SLE),rheumatoid arthritis, psoriatic arthritis, multiple vasculitides,idiopathic thrombocytopenic purpura (FTP), myasthenia gravis, allergicrhinitis, multiple sclerosis (MS), transplant rejection, Type Idiabetes, membranous nephritis, inflammatory bowel disease, autoimmunehemolytic anemia, autoimmune thyroiditis, cold and warm agglutinindiseases, Evans syndrome, hemolytic uremic syndrome/thromboticthrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjögren's syndrome,peripheral neuropathies, pemphigus vulgaris and asthma.

The present invention also provides a method of treating an IL-12,IL-23, and/or IFNα mediated disease (or use of the compounds of thepresent invention for the manufacture of a medicament for the treatmentof these diseases), comprising administering to a patient in need ofsuch treatment a therapeutically-effective amount of a compound offormula I.

The present invention also provides a method of treating an IL-12, IL-23and/or IFNα mediated disease (or use of the compounds of the presentinvention for the manufacture of a medicament for the treatment of thesediseases), comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound of formula I,wherein the IL-12, IL-23 and/or IFNα mediated disease is a diseasemodulated by IL-12, IL-23 and/or IFNα.

The present invention also provides a method of treating diseases,comprising administering to a patient in need of such treatment atherapeutically-effective amount of a compound of formula I incombination with other therapeutic agents.

The present invention also provides the compounds of the presentinvention for use in therapy.

In another embodiment, compounds of formula I are selected fromexemplified compounds or combinations of exemplified compounds or otherembodiments herein.

In another embodiment are compounds having an IC₅₀<1000 nM in at leastone of the assays described below.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects and/orembodiments of the invention noted herein. It is understood that any andall embodiments of the present invention may be taken in conjunctionwith any other embodiment or embodiments to describe additional morepreferred embodiments. It is also to be understood that each individualelement of the preferred embodiments is its own independent preferredembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of terms used in this specification andappended claims. The initial definition provided for a group or termherein applies to that group or term throughout the specification andclaims, individually or as part of another group, unless otherwiseindicated.

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis- andtrans-geometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated.

When any variable (e.g., R³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R³, then saidgroup may optionally be substituted with up to two R³ groups and R³ ateach occurrence is selected independently from the definition of R³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure.

A dash that is not between two letters or symbols is used to indicate apoint of attachment for a substituent. For example, —CONH₂ is attachedthrough the carbon atom.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I (e.g., an optionally substituted heteroarylgroup) refers to a moiety having 0, 1, 2, or more substituents. Forexample, “optionally substituted alkyl” encompasses both “alkyl” and“substituted alkyl” as defined below. It will be understood by thoseskilled in the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable.

As used herein, the term “at least one chemical entity” isinterchangeable with the term “a compound”.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

When the term “alkyl” is used together with another group, such as in“arylalkyl”, this conjunction defines with more specificity at least oneof the substituents that the substituted alkyl will contain. Forexample, “arylalkyl” refers to a substituted alkyl group as definedabove where at least one of the substituents is an aryl, such as benzyl.Thus, the term aryl(C₀₋₄)alkyl includes a substituted lower alkyl havingat least one aryl substituent and also includes an aryl directly bondedto another group, i.e., aryl(C₀)alkyl. The term “heteroarylalkyl” refersto a substituted alkyl group as defined above where at least one of thesubstituents is a heteroaryl.

When reference is made to a substituted alkenyl, alkynyl, alkylene,alkenylene, or alkynylene group, these groups are substituted with oneto three substituents as defined above for substituted alkyl groups.

The term “alkoxy” refers to an oxygen atom substituted by alkyl orsubstituted alkyl, as defined herein. For example, the term “alkoxy”includes the group —O—C₁₋₆alkyl such as methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, andthe like. “Lower alkoxy” refers to alkoxy groups having one to fourcarbons.

It should be understood that the selections for all groups, includingfor example, alkoxy, thioalkyl, and aminoalkyl, will be made by oneskilled in the field to provide stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo, or keto, (i.e., ═O)then 2 hydrogens on the atom are replaced. Keto substituents are notpresent on aromatic moieties. Unless otherwise specified, substituentsare named into the core structure. For example, it is to be understoodthat when (cycloalkyl)alkyl is listed as a possible substituent, thepoint of attachment of this substituent to the core structure is in thealkyl portion. Ring double bonds, as used herein, are double bonds thatare formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and subsequentformulation into an efficacious therapeutic agent. It is preferred thatthe presently recited compounds do not contain a N-halo, S(O)₂H, orS(O)H group.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. As used herein, “carbocycle” or“carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, or7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or13-membered bicyclic or tricyclic ring, any of which may be saturated,partially unsaturated, unsaturated or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl,cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl,cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl,indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). Asshown above, bridged rings are also included in the definition ofcarbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unlessotherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and phenyl. When the term “carbocycle” is used, it isintended to include “aryl”. A bridged ring occurs when one or morecarbon atoms link two non-adjacent carbon atoms. Preferred bridges areone or two carbon atoms. It is noted that a bridge always converts amonocyclic ring into a bicyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,and naphthyl groups, each of which may be substituted.

Accordingly, in compounds of formula I, the term “cycloalkyl” includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclooctyl, etc., as well as the following ring systems:

and the like, which optionally may be substituted at any available atomsof the ring(s). Preferred cycloalkyl groups include cyclopropyl,cyclopentyl, cyclohexyl, and

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

Thus, examples of aryl groups include:

(fluorenyl) and the like, which optionally may be substituted at anyavailable carbon or nitrogen atom. A preferred aryl group isoptionally-substituted phenyl.

The terms “heterocycle”, “heterocycloalkyl”, “heterocyclo”,“heterocyclic”, or “heterocyclyl” may be used interchangeably and referto substituted and unsubstituted 3- to 7-membered monocyclic groups, 7-to 11-membered bicyclic groups, and 10- to 15-membered tricyclic groups,in which at least one of the rings has at least one heteroatom (O, S orN), said heteroatom containing ring preferably having 1, 2, or 3heteroatoms selected from O, S, and N. Each ring of such a groupcontaining a heteroatom can contain one or two oxygen or sulfur atomsand/or from one to four nitrogen atoms provided that the total number ofheteroatoms in each ring is four or less, and further provided that thering contains at least one carbon atom. The nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen atoms may optionally bequaternized. The fused rings completing the bicyclic and tricyclicgroups may contain only carbon atoms and may be saturated, partiallysaturated, or fully unsaturated. The heterocyclo group may be attachedat any available nitrogen or carbon atom. As used herein the terms“heterocycle”, “heterocycloalkyl”, “heterocyclo”, “heterocyclic”, and“heterocyclyl” include “heteroaryl” groups, as defined below.

In addition to the heteroaryl groups described below, exemplarymonocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl,oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl,isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, 1-pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplarybicyclic heterocyclo groups include quinuclidinyl. Additional monocyclicheterocyclyl groups include

The term “heteroaryl” refers to substituted and unsubstituted aromatic5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups,and 11- to 14-membered tricyclic groups which have at least oneheteroatom (O, S or N) in at least one of the rings, saidheteroatom-containing ring preferably having 1, 2, or 3 heteroatomsselected from O, S, and N. Each ring of the heteroaryl group containinga heteroatom can contain one or two oxygen or sulfur atoms and/or fromone to four nitrogen atoms provided that the total number of heteroatomsin each ring is four or less and each ring has at least one carbon atom.The fused rings completing the bicyclic and tricyclic groups may containonly carbon atoms and may be saturated, partially saturated, orunsaturated. The nitrogen and sulfur atoms may optionally be oxidizedand the nitrogen atoms may optionally be quaternized. Heteroaryl groupswhich are bicyclic or tricyclic must include at least one fully aromaticring but the other fused ring or rings may be aromatic or non-aromatic.The heteroaryl group may be attached at any available nitrogen or carbonatom of any ring. As valence allows, if said further ring is cycloalkylor heterocyclo it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzindolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

In compounds of formula I, preferred heteroaryl groups include:

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl, piperidinyl, and morpholinyl) orheteroaryl (e.g., tetrazolyl, imidazolyl, pyrazolyl, triazolyl,thiazolyl, and furyl) the reference is intended to include rings having0 to 3, preferably 0 to 2, substituents selected from those recitedabove for the aryl, cycloalkyl, heterocyclo and/or heteroaryl groups, asappropriate.

The term “carbocyclyl” or “carbocyclic” refers to a saturated orunsaturated monocyclic or bicyclic ring in which all atoms of all ringsare carbon. Thus, the term includes cycloalkyl and aryl rings.Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofmono- and bicyclic carbocycles include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,phenyl and naphthyl. The carbocyclic ring may be substituted in whichcase the substituents are selected from those recited above forcycloalkyl and aryl groups.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

Throughout the specification, groups and substituents thereof may bechosen by one skilled in the field to provide stable moieties andcompounds and compounds useful as pharmaceutically-acceptable compoundsand/or intermediate compounds useful in makingpharmaceutically-acceptable compounds.

The compounds of formula I may exist in a free form (with no ionization)or can form salts which are also within the scope of this invention.Unless otherwise indicated, reference to an inventive compound isunderstood to include reference to the free form and to salts thereof.The term “salt(s)” denotes acidic and/or basic salts formed withinorganic and/or organic acids and bases. In addition, the term“salt(s)” may include zwitterions (inner salts), e.g., when a compoundof formula I, contains both a basic moiety, such as an amine or apyridine or imidazole ring, and an acidic moiety, such as a carboxylicacid. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, such as, for example, acceptable metaland amine salts in which the cation does not contribute significantly tothe toxicity or biological activity of the salt. However, other saltsmay be useful, e.g., in isolation or purification steps which may beemployed during preparation, and thus, are contemplated within the scopeof the invention. Salts of the compounds of the formula I may be formed,for example, by reacting a compound of the formula I with an amount ofacid or base, such as an equivalent amount, in a medium such as one inwhich the salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts; alkaline earth metal salts such ascalcium and magnesium salts; barium, zinc, and aluminum salts; saltswith organic bases (for example, organic amines) such as trialkylaminessuch as triethylamine, procaine, dibenzylamine,N-benzyl-P-phenethylamine, 1-ephenamine, N,N′-dibenzylethylene-diamine,dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamineor similar pharmaceutically acceptable amines and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quaternized with agents such as lower alkyl halides (e.g.,methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamylsulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others. Preferred salts includemonohydrochloride, hydrogensulfate, methanesulfonate, phosphate ornitrate salts.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically-acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples ofpharmaceutically-acceptable salts include, but are not limited to,mineral or organic acid salts of basic groups such as amines; and alkalior organic salts of acidic groups such as carboxylic acids. Thepharmaceutically-acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,and nitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically-acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.Stereoisomers may include compounds which are optical isomers throughpossession of one or more chiral atoms, as well as compounds which areoptical isomers by virtue of limited rotation about one or more bonds(atropisomers). The definition of compounds according to the inventionembraces all the possible stereoisomers and their mixtures. It veryparticularly embraces the racemic forms and the isolated optical isomershaving the specified activity. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates from the conventionalmethods, such as, for example, salt formation with an optically activeacid followed by crystallization.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

Prodrugs and solvates of the inventive compounds are also contemplated.The term “prodrug” denotes a compound which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of the formula I, and/or a salt and/orsolvate thereof. Any compound that will be converted in vivo to providethe bioactive agent (i.e., the compound for formula I) is a prodrugwithin the scope and spirit of the invention. For example, compoundscontaining a carboxy group can form physiologically hydrolyzable esterswhich serve as prodrugs by being hydrolyzed in the body to yield formulaI compounds per se. Such prodrugs are preferably administered orallysince hydrolysis in many instances occurs principally under theinfluence of the digestive enzymes. Parenteral administration may beused where the ester per se is active, or in those instances wherehydrolysis occurs in the blood. Examples of physiologically hydrolyzableesters of compounds of formula I include C₁₋₆alkylbenzyl,4-methoxybenzyl, indanyl, phthalyl, methoxymethyl,C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g., acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.,methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, EL, Chapter 5, “Design and Application of Prodrugs”,Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991); and

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992), each of which isincorporated herein by reference.

Compounds of the formula I and salts thereof may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that theall tautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans- andcis-isomers.

It should further be understood that solvates (e.g., hydrates) of thecompounds of Formula I are also with the scope of the present invention.Methods of solvation are generally known in the art.

Utility

The compounds of the invention modulate IL-23-stimulated andIFNα-stimulated cellular functions, including gene transcription. Othertypes of cellular functions that may be modulated by the compounds ofthe instant invention include, but are not limited to, IL-12-stimulatedresponses.

Accordingly, compounds of formula I have utility in treating conditionsassociated with the modulation of the function of IL-23 or IFNα, andparticularly the selective inhibition of function of IL-23, IL-12 and/orIFNα, by acting on Tyk2 to mediate signal transduction. Such conditionsinclude IL-23-, IL-12-, or IFNα-associated diseases in which pathogenicmechanisms are mediated by these cytokines.

As used herein, the terms “treating” or “treatment” encompass thetreatment of a disease state in a mammal, particularly in a human, andinclude: (a) preventing or delaying the occurrence of the disease statein a mammal, in particular, when such mammal is predisposed to thedisease state but has not yet been diagnosed as having it; (b)inhibiting the disease state, i.e., arresting its development; and/or(c) achieving a full or partial reduction of the symptoms or diseasestate, and/or alleviating, ameliorating, lessening, or curing thedisease or disorder and/or its symptoms.

In view of their activity as modulators of IL-23-, IL-12 andIFNα-stimulated cellular responses, compounds of Formula I are useful intreating IL-23-, IL-12- or IFNα-associated diseases including, but notlimited to, inflammatory diseases such as Crohn's disease, ulcerativecolitis, asthma, graft versus host disease, allograft rejection, chronicobstructive pulmonary disease; autoimmune diseases such as Graves'disease, rheumatoid arthritis, systemic lupus erythematosis, cutaneouslupus, lupus nephritis, discoid lupus erythematosus, psoriasis;auto-inflammatory diseases including CAPS, TRAPS, FMF, adult onsetstills, systemic onset juvenile idiopathic arthritis, gout, goutyarthritis; metabolic diseases including type 2 diabetes,atherosclerosis, myocardial infarction; destructive bone disorders suchas bone resorption disease, osteoarthritis, osteoporosis, multiplemyeloma-related bone disorder; proliferative disorders such as acutemyelogenous leukemia, chronic myelogenous leukemia; angiogenic disorderssuch as angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; infectious diseases suchas sepsis, septic shock, and Shigellosis; neurodegenerative diseasessuch as Alzheimer's disease, Parkinson's disease, cerebral ischemias orneurodegenerative disease caused by traumatic injury, oncologic andviral diseases such as metastatic melanoma, Kaposi's sarcoma, multiplemyeloma, and HIV infection and CMV retinitis, AIDS, respectively.

More particularly, the specific conditions or diseases that may betreated with the inventive compounds include, without limitation,pancreatitis (acute or chronic), asthma, allergies, adult respiratorydistress syndrome, chronic obstructive pulmonary disease,glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis,cutaneous lupus, lupus nephritis, discoid lupus erythematosus,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,diabetes, autoimmune hemolytic anemia, autoimmune neutropenia,thrombocytopenia, atopic dermatitis, chronic active hepatitis,myasthenia gravis, multiple sclerosis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease,inflammatory reaction induced by endotoxin, tuberculosis,atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acutesynovitis, pancreatic β-cell disease; diseases characterized by massiveneutrophil infiltration; rheumatoid spondylitis, gouty arthritis andother arthritic conditions, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoidosis, bone resorptiondisease, allograft rejections, fever and myalgias due to infection,cachexia secondary to infection, keloid formation, scar tissueformation, ulcerative colitis, pyresis, influenza, osteoporosis,osteoarthritis, acute myelogenous leukemia, chronic myelogenousleukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma,sepsis, septic shock, and Shigellosis; Alzheimer's disease, Parkinson'sdisease, cerebral ischemias or neurodegenerative disease caused bytraumatic injury; angiogenic disorders including solid tumors, ocularneovasculization, and infantile haemangiomas; viral diseases includingacute hepatitis infection (including hepatitis A, hepatitis B andhepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy,and herpes; stroke, myocardial ischemia, ischemia in stroke heartattacks, organ hyposia [should this be hypoxia], vascular hyperplasia,cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy,thrombin-induced platelet aggregation, endotoxemia and/or toxic shocksyndrome, conditions associated with prostaglandin endoperoxidasesyndase-2, and pemphigus vulgaris. Preferred methods of treatment arethose wherein the condition is selected from Crohn's disease, ulcerativecolitis, allograft rejection, rheumatoid arthritis, psoriasis,ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris.Alternatively preferred methods of treatment are those wherein thecondition is selected from ischemia reperfusion injury, includingcerebral ischemia reperfusions injury arising from stroke and cardiacischemia reperfusion injury arising from myocardial infarction. Anotherpreferred method of treatment is one in which the condition is multiplemyeloma.

When the terms “IL-23-, IL-12- and/or IFNα-associated condition” or“IL-23-, IL-12- and/or IFNα-associated disease or disorder” are usedherein, each is intended to encompass all of the conditions identifiedabove as if repeated at length, as well as any other condition that isaffected by IL-23, IL-12 and/or IFNα.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof atherapeutically-effective amount of at least one compound of Formula Ior a salt thereof. “Therapeutically effective amount” is intended toinclude an amount of a compound of the present invention that iseffective when administered alone or in combination to inhibit IL-23,IL-12 and/or IFNα function and/or treat diseases.

The methods of treating IL-23-, IL-12 and/or IFNα-associated conditionsmay comprise administering compounds of Formula I alone or incombination with each other and/or other suitable therapeutic agentsuseful in treating such conditions. Accordingly, “therapeuticallyeffective amount” is also intended to include an amount of thecombination of compounds claimed that is effective to inhibit IL-23,IL-12 and/or IFNα function and/or treat diseases associated with IL-23,IL-12 and/or IFNα.

Exemplary of such other therapeutic agents include corticosteroids,rolipram, calphostin, cytokine-suppressive anti-inflammatory drugs(CSAIDs), Interleukin-10, glucocorticoids, salicylates, nitric oxide,and other immunosuppressants; nuclear translocation inhibitors, such asdeoxyspergualin (DSG); non-steroidal anti-inflammatory drugs (NSAIDs)such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisoneor dexamethasone; antiviral agents such as abacavir; antiproliferativeagents such as methotrexate, leflunomide, FK506 (tacrolimus, PROGRAF®);anti-malarials such as hydroxychloroquine; cytotoxic drugs such asazathiprine and cyclophosphamide; TNF-α inhibitors such as tenidap,anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus orRAPAMUNE®) or derivatives thereof.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds. The present invention alsoprovides pharmaceutical compositions capable of treating IL-23-, IL-12-or IFNα-associated conditions by inhibiting Tyk2-mediated signaltransduction, including IL-23-, IL-12- and/or IFNα-mediated diseases, asdescribed above.

The inventive compositions may contain other therapeutic agents asdescribed above and may be formulated, for example, by employingconventional solid or liquid vehicles or diluents, as well aspharmaceutical additives of a type appropriate to the mode of desiredadministration (e.g., excipients, binders, preservatives, stabilizers,flavors, etc.) according to techniques such as those well known in theart of pharmaceutical formulation.

Accordingly, the present invention further includes compositionscomprising one or more compounds of Formula I and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include without limitationthe type and nature of the active agent being formulated; the subject towhich the agent-containing composition is to be administered; theintended route of administration of the composition; and, thetherapeutic indication being targeted. Pharmaceutically acceptablecarriers include both aqueous and non-aqueous liquid media, as well as avariety of solid and semi-solid dosage forms. Such carriers can includea number of different ingredients and additives in addition to theactive agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th Edition (1985), which is incorporated herein by referencein its entirety.

The compounds of Formula I may be administered by any means suitable forthe condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The therapeutically-effective amount of a compound of the presentinvention may be determined by one of ordinary skill in the art, andincludes exemplary dosage amounts for a mammal of from about 0.05 to1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species that are affected by modulation of IL-23, IL-12 and/orIFNα-mediated functions.

Methods of Preparation

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry.General synthetic schemes for preparing compounds of the presentinvention are described below. These schemes are illustrative and arenot meant to limit the possible techniques one skilled in the art mayuse to prepare the compounds disclosed herein. Different methods toprepare the compounds of the present invention will be evident to thoseskilled in the art. Additionally, the various steps in the synthesis maybe performed in an alternate sequence in order to give the desiredcompound or compounds. Examples of compounds of the present inventionprepared by methods described in the general schemes are given in thepreparations and examples section set out hereinafter.

EXAMPLES

Preparation of compounds of Formula (I), and intermediates used in thepreparation of compounds of Formula (I), can be prepared usingprocedures shown in the following Examples and related procedures. Themethods and conditions used in these examples, and the actual compoundsprepared in these Examples, are not meant to be limiting, but are meantto demonstrate how the compounds of Formula (I) can be prepared.Starting materials and reagents used in these examples, when notprepared by a procedure described herein, are generally eithercommercially available, or are reported in the chemical literature, ormay be prepared by using procedures described in the chemicalliterature.

In the Examples given, the phrase “dried and concentrated” generallyrefers to drying of a solution in an organic solvent over either sodiumsulfate or magnesium sulfate, followed by filtration and removal of thesolvent from the filtrate (generally under reduced pressure and at atemperature suitable to the stability of the material being prepared).Column chromatography was performed with pre-packed silica gelcartridges using an Isco medium pressure chromatography apparatus(Teledyne Corporation), eluting with the solvent or solvent mixtureindicated. The following abbreviations are used:

Abbreviations Abbreviation Meaning Ac acetyl ACN acetonitrile AcOHacetic acid anhyd. anhydrous aq. aqueous Bn benzyl Bu butyl Boctert-butoxycarbonyl BOP benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate CV Column Volumes DCE dichloroethane DCMdichloromethane DIC N,N′-Diisopropylcarbodiimide DMF dimethylformamideDMSO dimethylsulfoxide EtOAc ethyl acetate Et ethyl H or H₂ hydrogen h,hr or hrs hour(s) hex hexane i iso ISCO automated chromatography HOAc orAcOH acetic acid HCl hydrochloric acid HPLC high pressure liquidchromatography LC liquid chromatography LiHMDS Lithiumbis(trimethylsilyl)amide M molar mM millimolar Me methyl MeOH methanolMHz megahertz min. minute(s) mins minute(s) M + 1 (M + H)+ MS massspectrometry n or N normal nm nanometer nM nanomolar Pd/C palladium oncarbon Ph phenyl Pr propyl PSI pounds per square inch rb round bottle rtroom temperature Ret Time retention time sat. saturated SFCsupercritical fluid chromatography TBAF Tetra-n-butylammonium fluorideTEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Xantphos4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Preparations

The preparations set out below are for the synthesis of reagents thatwere not obtained from commercial sources and were employed for thepreparation of compounds of formula I of the invention. All chiralcompounds in the Tables and Schemes are racemic unless specifiedotherwise.

Reverse-phase preparative high performance liquid chromatography(“HPLC”) was performed with Shimadzu 8A liquid chromatographs using YMCS5 ODS columns (20×100, 20×250, or 30×250 millimeter (“mm”)). Gradientelution was performed with methanol (“MeOH”)/water mixtures in thepresence of 0.1% trifluoroacetic acid (“TFA”).

HPLC Methods

Method A:

Column: Waters Acquity BEH C₁₈ 2.0×50 mm, 1.7 μm; mobile phase A: waterwith 0.1% TFA; mobile phase B: MeCN with 0.1% TFA; temperature: 40° C.;flow rate 1 mL/min; gradient: 0-100% B over 1.5 min, then 0.5 minisocratic at 100% B.

QC-ACN-AA-XB: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

Method E:

Phenominex Kinetics C18, 2.1×50 mm, 2.1-μm particles; Mobile Phase A:5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase A: 10%acetonitrile in water with 0.1% TFA; mobile phase B: 90% acetonitrile inwater with 0.1% TFA; Temperature: 40° C.; Gradient: 0-100% B over 2minutes: UV at 220 nm.

Method F:

Column: YMC Combiscreen ODS-A 4.6×50 mm S-5; 5:95 acetonitrile:waterwith 10 mM ammonium acetate; mobile phase A: 10% methanol in water with0.1% TFA; mobile phase B: 90% methanol in water with 0.1% TFA;temperature: RT; flow rate 1 mL/min; gradient: 0-100% B over 4 min, then1 min isocratic at 100% B; UV at 254 nm.

Method OC-ACN-AA-XB:

Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile PhaseA: 5:95 acetonitrile: water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100%B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

Method OC-ACN-TFA-XB:

Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection: UV at 220 nm.

Method I:

Column: Sunfire C18 (4.6×150) mm, 3.5 μm; Mobile Phase A: 5:95acetonitrile: water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 10-100% B over 12minutes; Flow: 1 ml/min.

Method TS1:

Column: Waters Acquity UPLC BEH C18 (2.1×50 mm), 1.7 micron; SolventA=100% water with 0.05% TFA; Solvent B=100% acetonitrile with 0.05% TFA;gradient=2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flowrate: 0.8 mL/min;

Example 16-(cyclopropanecarboxamido)-4-((3-(4-((1,1-dioxidothiomorpholino)methyl)-1H-1,2,3-triazol-1-yl)-2-methoxyphenyl)amino)-N-(trideuteromethyl)pyridazine-3-carboxamide

Step 1

A mixture of 3-bromo-2-methoxyaniline (500 mg, 2.48 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (943 mg,3.71 mmol), KOAc (729 mg, 7.42 mmol) and PdCl₂(dppf) (91 mg, 0.124 mmol)in 1,4-dioxane (10 mL) was degassed by bubbling with nitrogen gas for 10minutes. The reaction mixture was sealed and heated to 100° C. for 4.5hours. Upon completion, the reaction was cooled to room temperature andloaded directly onto silica gel plug for purification by columnchromatography eluting in Hexanes/EtOAc 0-100%. The desired fractionswere concentrated and the material was further purified by silica gelcolumn chromatography eluting with DCM/MeOH 0-10% to give2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. LCMSm/z 250.0 (M+H)⁺; HPLC t_(R) 0.73 min (analytical HPLC Method TS1). ¹HNMR (400 MHz, CHLOROFORM-d) δ 7.12 (dd, J=7.3, 1.7 Hz, 1H), 6.96-6.91(m, 1H), 6.89-6.84 (m, 1H), 3.82 (s, 5H), 1.37 (s, 12H).

Step 2

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(295 mg, 1.41 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (387mg, 1.55 mmol) in THE (6 mL) was added LiHMDS (1M in THF, 3.53 mL, 3.53mmol). The reaction vial was stirred at 25° C. for 20 minutes. Uponcompletion, the reaction was quenched with saturated aqueous ammoniumchloride solution and diluted with DCM and water. The aqueous layer wasextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to give crude material that wasassumed quantitative of6-chloro-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(1.41 mmol) and used as such. LCMS m/z 422.1 (M+H)⁺; HPLC t_(R) 1.07 min(analytical HPLC Method TS1).

Step 3

A mixture of6-chloro-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(0.11 mmol, crude from Step 2), cyclopropanecarboxamide (50.5 mg, 0.593mmol), Pd2(dba)3 (10.9 mg, 0.012 mmol), Xantphos (13.7 mg, 0.024 mmol)and Cs₂CO₃ (97 mg, 0.296 mmol) in 1,4-dioxane (1 mL) was degassed bybubbling nitrogen gas through the mixture for 5 minutes. The reactionvessel was sealed and heated to 130° C. for 30 minutes. Upon completion,the reaction was cooled to room temperature and loaded directly ontosilica gel for purification by column chromatography eluting withDCM/MeOH 0-10% to give the desired product mixed with water solubleimpurities. The collected fractions were dissolved in DCM and washedwith water three times, dried over sodium sulfate, filtered, andconcentrated to afford6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(27 mg, 0.057 mmol, 52% yield) as a yellow solid. LCMS m/z 471.2 (M+H)+;HPLC tR 0.95 min (analytical HPLC Method TS1). 1H NMR (400 MHz,CHLOROFORM-d) □ 10.90 (s, 1H), 9.53 (br. s., 1H), 8.20-8.14 (m, 1H),8.03 (s, 1H), 7.56-7.50 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 3.82 (s, 3H),1.79 (ddd, J=12.3, 7.9, 4.4 Hz, 1H), 1.36 (s, 12H), 1.12-1.07 (m, 2H),0.92-0.86 (m, 2H)

Step 4

6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(20 mg, 0.043 mmol) was suspended in MeOH (0.3 mL), and sodium azide(5.5 mg, 0.085 mmol) and copper(II) acetate (1.9 mg, 0.011 mmol) wereadded. The reaction was stirred under an atmosphere of air at 65° C. for2.5 hours. Upon completion, the reaction was cooled to room temperatureand sodium ascorbate (2.1 mg, 0.011 mmol) and4-(prop-2-yn-1-yl)thiomorpholine 1,1-dioxide (29.5 mg, 0.170 mmol) wereadded sequentially. The reaction was stirred for 2 hours. Uponcompletion, the reaction was concentrated, taken up in DMF, filteredthrough a 0.45 micron syringe filter, and purified by preparative LC/MSwith the following conditions: Column: Waters XBridge C18, 19×200 mm,5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile: water with 0.1%trifluoroacetic acid; Gradient: 0-100% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. The fractions containing thedesired product were combined and dried via centrifugal evaporation togive6-(cyclopropanecarboxamido)-4-((3-(4-((1,1-dioxidothiomorpholino)methyl)-1H-1,2,3-triazol-1-yl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide,TFA (11.4 mg, 0.017 mmol, 38% yield). LCMS m/z 559.3 (M+H)⁺; HPLC t_(R)1.18 min (analytical HPLC Method QC-ACN-AA-XB). Select NMR peaks: ¹H NMR(500 MHz, DMSO-d₆) δ 11.40 (s, 1H), 11.08 (s, 1H), 9.17 (s, 1H), 8.56(s, 1H), 8.18 (s, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.51 (d, J=7.4 Hz, 1H),7.46-7.39 (m, 1H), 4.24 (s, 2H), 2.12-2.02 (m, 1H), 0.91-0.77 (m, 4H).

The Examples in Table 1 were prepared using a similar procedure used toprepare Example 1.

TABLE 1 Obs. QC Ex. MS Me- No. Structure MW Ion RT thod 2

510.6 511.4 1.19 QC- ACN- AA- XB 3

441.5 442.3 0.92 QC- ACN- TFA- XB 4

587.7 588.4 0.96 QC- ACN- TFA- XB 5

454.5 455.2 0.96 QC- ACN- AA- XB

Example 64-((3-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide

Step 1

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(605 mg, 2.89 mmol) and 3-amino-2-methoxybenzonitrile (472 mg, 3.18mmol) in THE (15 mL) was added LiHMDS (0.5M in 2-MeTHF, 18.52 mL, 9.26mmol). The reaction vial was stirred at 25° C. for 35 minutes. Uponcompletion, the reaction was quenched via addition of saturated aqueousammonium chloride solution, water, and DCM. The aqueous layer wasextracted with DCM. The combined organic layer was dried over sodiumsulfate, filtered, and concentrated to give material assumed to bequantitative yield of6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(2.89 mmol). Carried forward as such. LCMS m/z 321.0 (M+H)⁺; HPLC t_(R)0.84 min (analytical HPLC Method TS1).

Step 2

The material from Step 1(6-chloro-4-((3-cyano-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(2.89 mmol)), cyclopropanecarboxamide (1.23 g, 14.5 mmol), Pd₂(dba)₃(0.265 g, 0.289 mmol), Xantphos (0.334 g, 0.578 mmol) and Cs₂CO₃ (2.354g, 7.23 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogengas through the mixture for 5 minutes. The reaction vessel was sealedand heated to 130° C. for 45 minutes. Upon completion, the reactionmixture was diluted with DCM, filtered through a celite pad, andconcentrated. The crude isolate was then purified by columnchromatography on silica gel loading in DMF and eluting with DCM/MeOH0-10% to give fractions containing water-soluble impurities. The desiredfractions were combined and washed with water five times, dried oversodium sulfate, and concentrated to afford4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamidein assumed quantitative yield (2.76 mmol). Material was carried forwardas such. LCMS m/z 370.1 (M+H)⁺; HPLC t_(R) 0.78 min (analytical HPLCMethod TS1). ¹H NMR (400 MHz, DMSO-d₆) δ 11.37 (s, 1H), 10.99 (s, 1H),9.17 (s, 1H), 8.05 (s, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.61 (dd,J=7.9, 1.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 3.91 (s, 3H), 2.13-2.01 (m,1H), 0.90-0.75 (m, 4H)

Step 3

To a mixture of4-((3-cyano-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(0.541 mmol) and hydroxylamine hydrochloride (192 mg, 2.76 mmol) in EtOH(15 mL) was added potassium hydroxide (149 mg, 2.65 mmol). The mixturewas sealed and heated to 80° C. After 24 hours, another aliquot ofhydroxylamine hydrochloride (192 mg, 2.76 mmol) and potassium hydroxide(149 mg, 2.65 mmol) were each added and the reaction was heated for 90minutes more at 80° C. Upon completion, the reaction was cooled to roomtemperature, concentrated, taken up in DCM with a small amount of MeOHand filtered through a pad of celite. The filtrate was concentrated togive material in assumed quantitative yield of(Z)-6-(cyclopropanecarboxamido)-4-((3-(N′-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(0.541 mmol). Material was used as such. LCMS m/z 403.1 (M+H)⁺; HPLCt_(R) 0.55 min (analytical HPLC Method TS1).

Step 4

A portion of the material ( 1/10) from Step 3((Z)-6-(cyclopropanecarboxamido)-4-((3-(N′-hydroxycarbamimidoyl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(0.0541 mmol)) was suspended in DMF (0.5 mL) with2-((tert-butoxycarbonyl)amino)acetic acid (19 mg, 0.108 mmol). To thismixture was added DIC (0.020 mL, 0.130 mmol) at room temperature, andthe reaction was stirred for 90 minutes. Then, TBAF (1M in THF, 0.249mL, 0.249 mmol) was added in a single portion. After 4 hours, anotheraliquot of TBAF (1M in THF, 0.12 mL, 0.12 mmol) was added. After 16hours, the reaction was quenched via the addition of a few drops ofsaturated aqueous ammonium chloride solution, water and DCM. The aqueouslayer was extracted four times with 4/1 CHCl₃/iPrOH, and the combinedorganic layer was washed with water, dried over sodium sulfate, filteredand concentrated to afford material in assumed quantitative yield oftert-butyl((3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamate(0.0541 mmol). Used as such. LCMS m/z 542.3 (M+H)⁺; HPLC t_(R) 1.71 min(analytical HPLC Method QC-ACN-AA-XB).

Step 5

Half of the material from Step 4 (tert-butyl((3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)carbamate(0.0270 mmol) was suspended in DCM (0.5 mL) and TFA (0.5 mL) and stirredat room temperature for 1 hour. Upon completion, the reaction wasconcentrated. The crude residue was taken up in DMF with a few drops ofEt₃N to quench residual TFA. The material was purified via preparativeLC/MS with the following conditions: Column: Waters XBridge C18, 19×200mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mMammonium acetate; Gradient: 5-55% B over 20 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min. The fractions containing the desiredproduct were combined and dried via centrifugal evaporation to give4-((3-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(1.2 mg, 2.61 μmol, 9.66% yield). LCMS m/z 442.3 (M+H)⁺; HPLC t_(R) 1.11min (analytical HPLC Method QC-ACN-AA-XB). ¹H NMR (500 MHz, DMSO-d₆) δ11.34 (s, 1H), 11.00 (s, 1H), 9.13 (s, 1H), 8.12 (s, 1H), 7.69 (m, 2H),7.39 (t, J=8.0 Hz, 1H), 4.20 (s, 2H), 3.73 (s, 3H), 2.11-1.98 (m, 1H),0.89-0.71 (m, 4H).

The Examples in Table 2 were prepared using a similar procedure used toprepare Example 6.

TABLE 2 Obs. Ex. MS QC No. Structure MW Ion RT Method 7

511.6 512.1 0.86 QC- ACN- TFA-XB 8

494.5 495.1 1.33 QC- ACN- AA-XB 9

542.6 543.1 1.45 QC- ACN- AA-XB 10

542.6 543.3 1.12 QC- ACN- TFA-XB 11

558.6 559 0.98 QC- ACN- TFA-XB 12

559.6 560.3 1.48 QC- ACN- AA-XB 13

564.6 565.3 1.26 QC- ACN- TFA-XB 14

568.6 569.3 1.52 QC- ACN- AA-XB 15

588.7 589.5 1.42 QC- ACN- AA-XB 16

525.5 526.2 1.45 QC- ACN- AA-XB 17

483.5 484.3 1.16 QC- ACN- TFA-XB 18

580.7 581.3 1.05 QC- ACN- AA-XB 19

513.5 514.3 1.37 QC- ACN- AA-XB 20

573.6 574.3 1.11 QC- ACN- TFA-XB 21

566.6 567.4 1.1 QC- ACN- AA-XB 22

602.6 603.2 1.43 QC- ACN- AA-XB 23

539.6 540.4 1.27 QC- ACN- AA-XB 24

580.7 581.3 1.16 QC- ACN- AA-XB 25

553.6 554.3 1.33 QC- ACN- AA-XB 26

594.7 595.4 0.86 QC- ACN- TFA-XB 27

567.6 568.3 1.38 QC- ACN- TFA-XB 28

565.6 566.5 1.16 QC- ACN- TFA-XB 29

553.6 554.3 1.42 QC- ACN- AA-XB 30

499.5 500.1 1.14 QC- ACN- TFA-XB 31

483.5 484.1 0.99 QC- ACN- TFA-XB 32

519.6 520.1 1.08 QC- ACN- TFA-XB 33

541.6 542.2 1.49 QC- ACN- TFA-XB 34

610.7 611.4 1.85 QC- ACN- AA-XB 35

510.6 511.2 0.94 QC- ACN- TFA-XB 36

522.5 523.3 0.94 QC- ACN- TFA-XB 37

549.6 550.3 0.96 QC- ACN- AA-XB 38

502.5 503.2 1.1 QC- ACN- AA-XB 39

551.6 552.4 0.95 QC- ACN- TFA-XB 40

571.6 572.2 1.35 QC- ACN- AA-XB 41

555.6 556.2 1.46 QC- ACN- AA-XB 42

581.6 582.3 1.64 QC- ACN- AA-XB 43

569.6 570.3 1.37 QC- ACN- TFA-XB 44

516.5 517.1 1.32 QC- ACN- AA-XB 45

567.6 568.4 1.32 QC- ACN- TFA-XB 46

516.5 517.2 1.21 QC- ACN- AA-XB 47

516.5 517.1 1.21 QC- ACN- AA-XB 48

516.5 517.2 1.2 QC- ACN- AA-XB 49

528.5 529.2 1.25 QC- ACN- AA-XB 50

530.6 531.1 1.14 QC- ACN- TFA-XB 51

530.6 531.2 1.41 QC- ACN- AA-XB 52

530.6 531.1 1.22 QC- ACN- TFA-XB 53

542.6 543.1 1.37 QC- ACN- AA-XB 54

542.6 542.9 1.28 QC- ACN- TFA-XB 55

584.5 585 1.56 QC- ACN- AA-XB 56

538.6 539.2 1.36 QC- ACN- AA-XB 57

530.6 531.2 1.37 QC- ACN- AA-XB 58

544.6 545.2 1.27 QC- ACN- TFA-XB 59

530.6 531.2 1.38 QC- ACN- AA-XB 60

542.6 543.2 1.22 QC- ACN- TFA-XB 61

544.6 545.4 1.23 QC- ACN- TFA-XB 62

558.6 559.1 1.14 QC- ACN- AA-XB 63

452.5 453.1 1.34 QC- ACN- AA-XB 64

487.5 488 0.96 QC- ACN- TFA-XB 65

533.6 534.1 1.17 QC- ACN- TFA-XB 66

558.6 559.3 0.93 QC- ACN- TFA-XB 67

439.4 440.1 1.37 QC- ACN- AA-XB 68

528.5 529.1 1.26 QC- ACN- AA-XB 69

442.5 443.3 0.95 QC- ACN- TFA-XB 70

425.4 426.2 0.85 QC- ACN- TFA-XB 71

501.5 502.1 0.97 QC- ACN- TFA-XB 72

456.5 457.2 1.65 QC- ACN- AA-XB 73

470.5 471 1.18 QC- ACN- TFA-XB 74

468.5 469.3 1.39 QC- ACN- AA-XB 75

575.6 576.2 1.06 QC- ACN- TFA-XB 76

545.6 546.2 1.11 QC- ACN- TFA-XB 77

511.5 512.2 1.24 QC- ACN- AA-XB 78

518.6 519.3 1.08 QC- ACN- AA-XB 79

509.5 510.3 1.37 QC- ACN- TFA-XB 80

497.5 498.2 1.11 QC- ACN- TFA-XB 81

482.5 483.2 1.31 QC- ACN- AA-XB 82

511.6 512.2 0.79 QC- ACN- TFA-XB 83

525.6 526 1.22 QC- ACN- AA-XB 84

456.5 457 1.29 QC- ACN- TFA-XB 85

456.5 457 1.46 QC- ACN- AA-XB 86

469.5 470.4 1.23 QC- ACN- TFA-XB 87

457.5 458.3 1.53 QC- ACN- AA-XB 88

443.5 444 1.12 QC- ACN- TFA-XB 89

483.5 484.2 1.73 QC- ACN- AA-XB 90

469.5 470.2 1.43 QC- ACN- AA-XB 91

469.5 470.2 1.56 QC- ACN- AA-XB 92

567.6 568.2 1.42 QC- ACN- AA-XB 93

455.5 456 1.08 QC- ACN- TFA-XB 94

532.6 533.2 1.31 QC- ACN- AA-XB 95

587.7 588 1.5 QC- ACN- AA-XB 96

510.6 511.1 1.29 QC- ACN- AA-XB 97

544.6 545.1 1.3 QC- ACN- AA-XB 98

441.5 442.2 1.19 QC- ACN- TFA-XB 99

478.5 479.1 1.5 QC- ACN- AA-XB 100

492.6 493.2 1.79 QC- ACN- AA-XB 101

410.4 411.1 1.1 QC- ACN- AA-XB 102

465.5 466.4 0.76 QC- ACN- AA-XB 103

487.5 488.2 0.7 QC- ACN- TFA-XB 104

467.5 468.4 1.12 QC- ACN- AA-XB 105

483.5 484.1 1.15 QC- ACN- AA-XB 106

438.4 439.2 0.88 QC- ACN- AA-XB 107

426.4 427.4 0.91 QC- ACN- AA-XB 108

425.5 426.3 0.51 QC- ACN- TFA-XB 109

503.5 504.2 0.95 QC- ACN- AA-XB 110

419.4 420.3 0.85 QC- ACN- AA-XB 111

411.4 412.2 0.99 QC- ACN- AA-XB 112

488.5 489.2 1.05 QC- ACN- AA-XB 113

468.5 469.4 1.14 QC- ACN- AA-XB 114

439.4 440.4 0.91 QC- ACN- AA-XB 115

481.5 482.2 0.73 QC- ACN- AA-XB 116

467.5 468.3 0.55 QC- ACN- TFA-XB 117

466.5 467.2 0.79 QC- ACN- AA-XB 118

474.5 475.1 1.13 QC- ACN- AA-XB 119

488.5 489.3 1.22 QC- ACN- AA-XB

Example 1204-((3-(3-((4-acetylpiperazin-1-yl)methyl)-1,2,4-oxadiazol-5-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-trideuteromethylpyridazine-3-carboxamide

Step 1

A mixture of tert-butyl piperazine-1-carboxylate (0.931 g, 5 mmol),bromoacetonitrile (0.348 mL, 5.00 mmol) and potassium carbonate (1.037g, 7.50 mmol) in DMF (20 mL) was stirred at rt for 18 hr. The reactionmixture was partitioned between EtOAc (75 ml) and water (75 ml). Theorganic layer was washed with 10% LiCl solution (2×75 ml) and brine (75ml). After drying (Na₂SO₄) and filtration, the organic layer wasconcentrated to afford tert-butyl4-(cyanomethyl)piperazine-1-carboxylate (1.08 g, 4.79 mmol, 96% yield)as a dark yellow solid. ¹H NMR (400 MHz, chloroform-d) δ 3.53 (s, 2H),3.51-3.45 (m, 4H), 2.60-2.47 (m, 4H), 1.47 (s, 9H).

Step 2

A mixture of tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (1.07 g,4.75 mmol), hydroxylamine hydrochloride (0.495 g, 7.12 mmol) and sodiumbicarbonate (0.798 g, 9.50 mmol) in tert-BuOH (20 mL) was stirred at 80°C. for 4 hr. After cooling to rt, the reaction mixture was partitionedbetween EtOAc (75 ml) and water (75 ml). The organic layer was washedwith brine (50 ml), dried (Na₂SO₄) and concentrated to afford(Z)-tert-butyl 4-(2-amino-2-(hydroxyimino)ethyl)piperazine-1-carboxylate(987 mg, 3.82 mmol, 80% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.97 (s, 1H), 5.22 (s, 2H), 3.38-3.27 (m, 6H), 2.32-2.25 (m,4H), 1.43-1.35 (m, 9H).

Step 3

A mixture of methyl 2-hydroxy-3-nitrobenzoate (6 g, 30.4 mmol),iodomethane (3.81 mL, 60.9 mmol) and potassium carbonate (10.52 g, 76mmol) in DMF (100 mL) was stirred at rt for 3 days. Ice water (500 ml)was added and the resulting suspension was stirred for 30 minutes.Filtration and drying afforded methyl 2-methoxy-3-nitrobenzoate (5.17 g,24.48 mmol, 80% yield) as a white solid. LCMS m/z 219.1 (M+H)⁺; HPLCt_(R) 1.46 min (analytical HPLC Method F); ¹H NMR (400 MHz,chloroform-d) δ 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.91 (dd, J=8.1, 1.8 Hz,1H), 7.31-7.24 (m, 1H), 4.01 (s, 3H), 3.96 (s, 3H).

Step 4

A mixture of methyl 2-methoxy-3-nitrobenzoate (5.16 g, 24.44 mmol) andNaOH, 1N (51.3 mL, 51.3 mmol) in MeOH (200 mL) was stirred at rt for 18hr. The MeOH was removed on the rotovap and the remaining solution wasdiluted with 100 ml of water. The pH was adjusted to 1 with 1N HCl andthe resulting suspension was filtered and dried to afford2-methoxy-3-nitrobenzoic acid (4.65 g, 23.59 mmol, 97% yield) as a whitesolid. LCMS m/z 198.0 (M+H)⁺; HPLC t_(R) 1.01 min (analytical HPLCMethod F); ¹H NMR (400 MHz, chloroform-d) δ 8.30 (dd, J=7.9, 1.8 Hz,1H), 8.04 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 4.09 (s, 3H)carboxylic acid proton not seen.

Step 5

To a mixture of 2-methoxy-3-nitrobenzoic acid (4.55 g, 23.08 mmol),4-dimethylaminopyridine (0.282 g, 2.308 mmol) and tert-butanol (3.31 mL,34.6 mmol) in DCM (200 mL) at 0° C. was added dicyclohexylcarbodiimide(4.76 g, 23.08 mmol) in 2 portions. The reaction mixture was allowed towarm and was stirred at rt for 16 hrs. After filtration through celite,the filtrate was washed with 1N HCl (2×200 ml) and brine (200 ml). Afterdrying (MgSO₄) and filtration the organic layer was concentrated to ayellow semi-solid that was chromatographed on a 120 gm ISCO silica gelcartridge, eluting with a 0-30% EtOAc/Hex gradient. The pure fractionswere concentrated to afford tert-butyl 2-methoxy-3-nitrobenzoate (5.11g, 20.18 mmol, 87% yield) as a light yellow oil. ¹H NMR (400 MHz,chloroform-d) δ 7.94 (dd, J=7.9, 1.8 Hz, 1H), 7.87 (dd, J=7.9, 1.8 Hz,1H), 7.30-7.20 (m, 1H), 4.00 (s, 3H), 1.63 (s, 9H).

Step 6

A mixture of tert-butyl 2-methoxy-3-nitrobenzoate (5.1 g, 20.14 mmol)and 10% Pd/C (1.072 g, 1.007 mmol) in ethyl acetate (200 ml) was stirredunder an atmosphere of hydrogen at rt for 16 hr. Filtration through a0.45 micron nylon filter and concentration of the filtrate affordedtert-butyl 3-amino-2-methoxybenzoate (4.50 g, 20.16 mmol, 100% yield) asa yellow oil, The material became a crystalline solid upon standing. ¹HNMR (400 MHz, chloroform-d) δ 7.11 (dd, J=7.7, 1.8 Hz, 1H), 6.96-6.89(m, 1H), 6.88-6.83 (m, 1H), 3.90 (br s, 2H), 3.84 (s, 3H), 1.60 (s, 9H)

Step 7

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(see previous patents for preparation) (1 g, 4.78 mmol) and tert-butyl3-amino-2-methoxybenzoate (1.067 g, 4.78 mmol) in THE (30 mL) at rt wasadded dropwise over 5 minutes LiHMDS, 1M in (11.96 mL, 11.96 mmol). Theresulting solution was stirred at rt for 10 minutes. The reactionmixture was quenched with 10 ml of saturated ammonium chloride solution.The resulting mixture was partitioned between EtOAc (150 ml) andsaturated ammonium chloride solution (150 ml). The organic layer waswashed with brine (150 ml), dried (Na₂SO₄) and concentrated to an amberoil that was chromatographed on a 80 gm ISCO silica gel cartridge,eluting with a 0-60% EtOAc/Hex gradient. The pure fractions wereconcentrated to afford tert-butyl3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(1.60 g, 4.04 mmol, 84% yield) as a light yellow solid. LCMS m/z396.4/398.2 (M+H)⁺; HPLC t_(R) 2.93 min (analytical HPLC Method F)

Step 8

A mixture of tert-butyl3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(1.2 g, 3.03 mmol), cyclopropanecarboxamide (0.516 g, 6.06 mmol),Pd₂(dba)₃, chloroform adduct (0.313 g, 0.303 mmol), Xantphos (0.351 g,0.606 mmol) and Cs₂CO₃ (3.95 g, 12.13 mmol) in Dioxane (20 mL) wasdegassed by bubbling nitrogen through the mixture for 5 minutes. Thereaction vessel was sealed and heated to 130° C. for 6 hr. After coolingto rt, the reaction mixture was partitioned between EtOAc (100 ml) andwater (50 ml). The aqueous layer was extracted with EtOAc (50 ml) andthe combined organics were dried (Na₂SO₄) and concentrated to afford ayellow oil that was chromatographed on a 80 gm ISCO silica gelcartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractionswere concentrated to afford tert-butyl3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(1.01 g, 2.272 mmol, 75.0% yield) as a yellow solid. LCMS m/z 445.5(M+H)⁺; HPLC t_(R) 2.59 min (analytical HPLC Method F).

Step 9

A mixture of tert-butyl3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoate(1.01 g, 2.272 mmol) and HCl, 4N in dioxane (5.68 mL, 22.72 mmol) in DCM(10 mL) was stirred at rt for 8 hr. The reaction mixture was allowed tostand in the freezer for 3 days. The volatiles were removed in vacuo andthe residue was dried to afford((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoicacid, HCl (0.96 g, 2.260 mmol, 99% yield) as a yellow solid. LCMS m/z389.3 (M+H)⁺; HPLC t_(R) 1.48 min (analytical HPLC Method F).

Step 10

A mixture of3-((6-(cyclopropanecarboxamido)-3-(trideutero-methylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoicacid (350 mg, 0.901 mmol), (Z)-tert-butyl4-(2-amino-2-(hydroxyimino)ethyl)piperazine-1-carboxylate (233 mg, 0.901mmol), 3-(Ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine, HCl (190mg, 0.991 mmol), 1-hydroxybenzotriazole (152 mg, 0.991 mmol) andtriethylamine (377 μl, 2.70 mmol) in DMF was stirred 18 hr at rt. Anadditional amount equal to half of the initial aliquot of each reagent(except starting material) was added and stirring was continued at rtfor 3 days. An additional amount of (Z)-tert-butyl4-(2-amino-2-(hydroxyimino)ethyl)piperazine-1-carboxylate (100 mg) wasadded followed by BOP (199 mg, 0.451 mmol) and the mixture was stirred 1hr at rt. The reaction mixture was partitioned between EtOAc (40 ml) andwater (40 ml). The organic layer was washed with 10% LiCl solution (2×40ml) and brine (40 ml). After drying (Na₂SO₄) and filtration the organiclayer was concentrated to afford (Z)-tert-butyl4-(2-amino-2-(((3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoyl)oxy)imino)ethyl)piperazine-1-carboxylate(565 mg, 0.899 mmol, 100% yield) as a yellow solid. LCMS m/z 629.5(M+H)⁺; HPLC t_(R) 2.28 min (analytical HPLC Method F).

Step 11

A mixture of (Z)-tert-butyl4-(2-amino-2-(((3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoyl)oxy)imino)ethyl)piperazine-1-carboxylate (565 mg, 0.899 mmol) andtetrabutylammonium fluoride, 1M in THE (1.348 mL, 1.348 mmol) inacetonitrile (9 mL) was stirred at rt for 16 hr. The reaction mixturewas partitioned between EtOAc (30 ml) and waster (30 ml). An emulsionformed. ˜1 gm of NaCl was added and the layers separated. The organiclayer was washed with brine (30 ml). After drying (Na₂SO₄) andfiltration, the organic layer was concentrated to afford a yellow oilthat was chromatographed on a 24 gm ISCO silica gel cartridge, elutingwith a 0-100% EtOAc/Hex gradient. The pure fractions were concentratedto afford tert-butyl4-((5-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)piperazine-1-carboxylate(213 mg, 0.349 mmol, 38.8% yield) as an off-white solid. LCMS m/z 611.5(M+H)⁺; HPLC t_(R) 2.35 min (analytical HPLC Method F).

Step 12

A mixture of tert-butyl4-((5-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methyl)piperazine-1-carboxylate(201 mg, 0.329 mmol) and HCl, 4N in dioxane (0.823 mL, 3.29 mmol) in DCM(4 mL) was allowed to stand at rt overnight. Removal of the volatiles invacuo and drying afforded6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide,HCl (180 mg, 0.329 mmol, 100% yield) as a yellow solid. LCMS m/z 511.5(M+H)⁺; HPLC t_(R) 1.91 min (analytical HPLC Method F).

Step 13

A mixture of6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-(piperazin-1-ylmethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide,HCl (12 mg, 0.022 mmol), acetic anhydride (2.277 μl, 0.024 mmol) andtriethylamine (0.012 ml, 0.088 mmol) in DCM (0.25 ml) was agitated at rtfor 1 hr. MeOH (0.2 ml) was added and the volatiles were removed invacuo. The residue was dissolved in DMSO and was purified viapreparative LC/MS with the following conditions: Column: waters xbridgec-18, 19×100 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 10-80% B over 12 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporationto afford4-((3-(3-((4-acetylpiperazin-1-yl)methyl)-1,2,4-oxadiazol-5-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(10.3 mg, 0.0.018 mmol, 84% yield). LCMS m/z 553.2 (M+H)⁺; HPLC t_(R)1.25 min (QC-ACN-AA-XB); ¹H NMR (500 MHz, DMSO-d₆) δ 11.36 (s, 1H),11.05 (s, 1H), 9.16 (s, 1H), 8.12 (s, 1H), 7.83 (d, J=7.4 Hz, 1H), 7.77(d, J=8.1 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 3.81 (s, 2H), 3.78 (s, 3H),3.44 (d, J=4.7 Hz, 1H), 2.55 (d, J=4.7 Hz, 2H), 2.13-2.02 (m, 1H), 1.97(s, 3H), 0.90-0.75 (m, 4H). Missing peaks co-resonate with solvent andwater peaks.

The Examples in Table 3 were prepared using a similar procedure used toprepare Example 120.

TABLE 3 Obs. Ex. MS QC No. Structure MW Ion RT Method 121

440.5 441.3 1.44 QC- ACN- TFA-XB 122

468.5 469.3 2.02 QC- ACN-AA- XB 123

488.5 489.3 1.74 QC- ACN- TFA-XB 124

511.6 512.3 1.33 QC- ACN-AA- XB 125

510.6 511.2 1.28 QC- ACN-AA- XB 126

510.6 511.3 1.1 QC- ACN-AA- XB 127

582.6 583.2 1.26 QC- ACN-AA- XB 128

588.7 589.3 1.45 QC- ACN-AA- XB 129

564.6 565.2 1.33 QC- ACN-AA- XB 130

615.7 616.2 1.34 QC- ACN-AA- XB 131

615.7 616.4 0.94 QC- ACN- TFA-XB 132

578.6 579.4 1.53 QC- ACN-AA- XB 133

603.7 604.2 1.44 QC- ACN-AA- XB 134

577.6 578.4 1.41 QC- ACN-AA- XB 135

610.7 611.4 1.94 QC- ACN-AA- XB 136

581.7 582.3 1.37 QC- ACN-AA- XB 137

624.7 625.3 1.7 QC- ACN-AA- XB 138

568.6 569.3 1.46 QC- ACN-AA- XB 139

591.6 592.4 1.17 QC- ACN-AA- XB 140

566.6 567.3 1.13 QC- ACN-AA- XB 141

602.6 603.3 1.25 QC- ACN-AA- XB 142

541.6 542.3 1.74 QC- ACN-AA- XB 143

441.5 442.2 1.13 QC- ACN-AA- XB 144

532.6 533.3 1.67 QC- ACN- TFA-XB 145

483.5 484.2 1.16 QC- ACN-AA- XB 146

519.6 520. 1.08 QC- ACN- TFA-XB 147

526.6 527.2 1.23 QC- ACN-AA- XB 148

508.5 509.2 1.02 QC- ACN- TFA-XB 149

539.6 540.2 1.35 QC- ACN-AA- XB 150

567.6 568.3 1.82 QC- ACN-AA- XB 151

534.6 535.2 1.26 QC- ACN-AA- XB 152

513.5 514.2 1.05 QC- ACN- TFA-XB 153

612.7 613.3 1.5 QC- ACN-AA- XB 154

512.5 513.1 0.81 QC- ACN- TFA-XB 155

498.5 499.2 0.8 QC- ACN- TFA-XB 156

467.5 468.2 0.86 QC- ACN- TFA-XB 157

598.6 599.3 1.45 QC- ACN-AA- XB 158

539.6 540.1 1.58 QC- ACN-AA- XB 159

568.6 569.1 1.21 QC- ACN-AA- XB 160

581.7 582.1 1.03 QC- ACN-AA- XB 161

667.7 668.2 1.13 QC- ACN- TFA-XB 162

567.6 568.3 0.94 QC- ACN-AA- XB 163

645.7 646.4 0.94 QC- ACN- TFA-XB 164

559.6 560.0 1.27 QC- ACN-AA- XB 165

509.5 510.2 1.07 QC- ACN- TFA-XB 166

545.6 546.3 1.37 QC- ACN-AA- XB 167

555.6 556.3 1.65 QC- ACN- TFA-XB 168

455.5 456.2 0.85 QC- ACN- TFA-XB 169

533.6 534.2 1.23 QC- ACN- TFA-XB 170

527.6 528.2 1.29 QC- ACN-AA- XB 171

522.5 523.2 1.3 QC- ACN-AA- XB 172

540.6 541.3 1.26 QC- ACN-AA- XB 173

497.5 498.3 1.26 QC- ACN-AA- XB 174

442.5 443. 1.18 QC- ACN-AA- XB 175

557.6 558.1 1.58 QC- ACN-AA- XB 176

527.6 528.2 1.23 QC- ACN-AA- XB 177

513.5 514.2 1.09 QC- ACN-AA- XB 178

497.5 498.2 1.06 QC- ACN- TFA-XB 179

539.6 540.0 1.23 QC- ACN-AA- XB 180

524.6 525.3 1.05 QC- ACN-AA- XB 181

455.5 456.0 1.1 QC- ACN-AA- XB 182

5135 514.2 1.38 QC- ACN- AA-XB 183

497.5 498.4 1.01 QC- ACN- TFA-XB 184

533.6 534.0 1.32 QC- ACN-AA- XB 185

641.7 642.4 2.21 QC- ACN-AA- XB 186

470.5 471.2 1.38 QC- ACN-AA- XB 187

527.6 528.2 1.16 QC- ACN-AA- XB 188

543.6 544.2 1.29 QC- ACN-AA- XB 189

485.5 486.4 1.07 QC- ACN-AA- XB 190

541.6 542.3 1.04 QC- ACN- TFA-XB 191

455.5 456.4 1.14 QC- ACN-AA- XB 192

513.5 514.2 1.2 QC- ACN- TFA-XB 193

555.6 556.3 1.76 QC- ACN-AA- XB 194

497.5 498.2 1.21 QC- ACN-AA- XB 195

533.6 534.2 1.33 QC- ACN-AA- XB 196

511.6 512.3 1.32 QC- ACN-AA- XB 197

627.7 628.3 1.85 QC- ACN- TFA-XB 198

527.6 528.2 1.13 QC- ACN-AA- XB 199

513.5 514.1 1.1 QC- ACN-AA- XB 200

555.6 556. 0 1.41 QC- ACN-AA- XB 201

471.5 472.2 0.8 QC- ACN- TFA-XB 202

543.6 544.2 0.99 QC- ACN- TFA-XB 203

527.6 528.1 1.16 QC- ACN-AA- XB 204

485.5 486.2 1.07 QC- ACN-AA- XB 205

557.6 558.2 1.07 QC- ACN- TFA-XB 206

641.7 642.2 1.99 QC- ACN- TFA-XB 207

525.6 526.2 0.83 QC- ACN- TFA-XB 208

541.6 542.2 1.06 QC- ACN- TFA-XB 209

495.6 496.2 1.45 QC- ACN-AA- XB 210

538.6 539.2 1.61 QC- ACN-AA- XB 211

523.6 524.2 1.12 QC- ACN- TFA-XB 212

466.5 467.2 1.34 QC- ACN-AA- XB 213

566.6 567.1 1.71 QC- ACN-AA- XB 214

508.6 509.1 0.91 QC- ACN- TFA-XB 215

494.6 495.2 1.51 QC- ACN-AA- XB 216

531.6 532.2 1.83 QC- ACN-AA- XB 217

441.5 442.1 0.83 QC- ACN- TFA-XB 218

469.5 470.2 1.39 QC- ACN-AA- XB 219

627.7 628.4 2.09 QC- ACN-AA- XB 220

513.5 514.3 1.03 QC- ACN-AA- XB 221

471.5 472.2 1 QC- ACN-AA- XB 222

565.6 566.2 1.28 QC- ACN-AA- XB 223

601.7 602.3 1.4 QC- ACN-AA- XB 224

514.6 515.5 1.06 E 225

456.5 457.2 1.31 QC- ACN-AA- XB 226

512.6 513.2 1.6 QC- ACN- TFA-XB 227

511.6 512.2 1.76 QC- ACN-AA- XB 228

455.5 456.2 1.11 QC- ACN-AA- XB 229

452.5 453.1 1.86 QC- ACN-AA- XB 230

529.5 530.2 1.53 QC- ACN-AA- XB 231

636.7 637.5 1.92 QC- ACN-AA- XB 232

536.6 537.2 0.72 QC- ACN- TFA-XB 233

578.6 579.2 1.34 QC- ACN-AA- XB 234

594.6 595.4 1.56 QC- ACN-AA- XB 235

614.7 615.1 1.23 QC- ACN-AA- XB 236

514.6 515.0 2.14 QC- ACN-AA- XB 237

535.6 536.3 0.81 QC- ACN- TFA-XB 238

551.6 552.3 0.88 QC- ACN- TFA-XB

Example 2395-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-NAN-dimethylthiazole-2-carboxamide

Step 1

A stirred mixture of ethyl 2-bromothiazole-5-carboxylate (116 mg, 0.491mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(135 mg, 0.540 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (16.01 mg, 0.025 mmol) in Dioxane (4 mL) wasdegassed by bubbling nitrogen through the mixture for 5 minutes. 2MK3PO₄ (aq) (0.737 mL, 1.474 mmol) was quickly added and the reactionmixture heated at 100° C. for one hour. LC-MS showed complete conversionto the desired product mass. The reaction mixture was cooled to roomtemperature. The reaction mixture was diluted with EtOAc (75 mL) andthen dried over sodium sulfate, filtered, concentrated and purified byflash chromatography, eluting with 0-100% EtOAc in hexanes. Thisafforded ethyl 2-(3-amino-2-methoxyphenyl)thiazole-5-carboxylate (84 mg,0.299 mmol, 60.8% yield) as a yellow oil. LCMS m/z 279.2 (M+H)⁺; HPLCt_(R) 0.86 min (HPLC Method A).

Step 2

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(62 mg, 0.297 mmol) and ethyl2-(3-amino-2-methoxyphenyl)thiazole-5-carboxylate (83 mg, 0.297 mmol) inTetrahydrofuran (2.5 mL) at rt was added dropwise over 5 minutes LiHMDS,1M (0.741 mL, 0.741 mmol). The resulting solution was stirred at rt for30 minutes. The reaction mixture was quenched with 1 ml of saturatedNH₄Cl solution. The resulting mixture was partitioned between EtOAc (30ml) and saturated NH₄Cl solution (30 ml). The organic layer was washedwith brine (30 ml), dried (Na₂SO₄) and concentrated to an amber oil thatwas chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a0-60% EtOAc/Hex gradient. The pure fractions were concentrated to affordethyl2-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylate(80 mg, 0.176 mmol, 59.2% yield) as a white solid. LCMS m/z 451.2(M+H)⁺; HPLC t_(R) 1.02 min (analytical HPLC Method A).

Step 3

A mixture of4-(3-((2-chloro-5-(trideuteromethylcarbamoyl)pyridin-4-yl)amino)-5-fluoro-2-methoxyphenyl)-N-(2-methoxyethyl)thiazole-2-carboxamide(80 mg, 0.177 mmol), Xantphos (20.53 mg, 0.035 mmol), andcyclopropanecarboxamide (75 mg, 0.887 mmol) in dioxane (3 mL) wasdegassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (231 mg,0.710 mmol) and Pd₂(dba)₃ (16.25 mg, 0.018 mmol) were added, the vesselwas sealed, and the reaction was stirred at 130° C. for 45 minutes. Thereaction was complete by LC-MS. The reaction was cooled to roomtemperature, then concentrated and loaded directly onto a 12 g ISCOcolumn for purification by flash chromatography, eluting with 0-15% MeOHin DCM. This afforded ethyl2-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylate(66 mg, 0.129 mmol, 73.0% yield) as a pale yellow solid. LCMS m/z 500.2(M+H)⁺; HPLC t_(R) 0.89 min (analytical HPLC Method A)

Step 4

To a solution of ethyl2-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylate(41 mg, 0.082 mmol) in THE (2 ml) was added a solution of lithiumhydroxide, H₂O (4.13 mg, 0.098 mmol) in water (0.5 mL). The resultingsolution was stirred at room temperature over the weekend. The volatileswere removed in vacuo to afford2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d₃)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylicacid, lithium salt (38 mg, 0.081 mmol, 98% yield) as a yellow solid.Used as is. LCMS m/z 472.4 (M+H)⁺; HPLC t_(R) 0.72 min (analytical HPLCMethod A).

Step 5

A mixture of2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d₃)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)thiazole-5-carboxylicacid, lithium salt (13 mg, 0.028 mmol), dimethylamine, 2M in THE (0.069mL, 0.138 mmol), BOP (18.29 mg, 0.041 mmol) and Et₃N (0.019 mL, 0.138mmol) in DMF (0.5 mL) was agitated at rt overnight. The reaction wascomplete by LC-MS, so the reaction was diluted to 1.5 mL with methanol,then filtered and submitted for purification. This afforded2-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-N,N-dimethylthiazole-5-carboxamide(1.9 mg, 3.70 μmol, 13.41% yield) LCMS m/z 499.5 (M+H)⁺; HPLC t_(R) 0.72min (analytical HPLC Method A); ¹H NMR (500 MHz, DMSO-d₆) δ 11.35 (s,1H), 10.96 (s, 1H), 9.18 (s, 1H), 8.30 (s, 1H), 8.12 (br d, J=8.1 Hz,1H), 8.06 (s, 1H), 7.59 (br d, J=7.7 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H),3.80 (s, 3H), 3.53-3.40 (m, 3H), 3.25 (br s, 2H), 3.17 (br s, 1H), 3.04(br s, 2H), 2.56-2.53 (m, 1H), 2.06 (br s, 1H), 0.86-0.77 (m, 4H)

The Examples in Table 4 were prepared using a similar procedure used toprepare Example 239.

TABLE 4 Obs. Ex. MS QC No. Structure MW Ion RT Method 240

569.7 570.2 1.29 QC- ACN- AA-XB 241

629.7 630.3 1.36 QC- ACN- TFA-XB 242

631.7 632.5 1.44 QC- ACN- AA-XB 243

495.6 496.2 0.99 QC- ACN- TFA-XB 244

537.6 538.2 1.08 QC- ACN- TFA-XB 245

523.6 524.2 5.8 I 246

481.5 482.1 5.8 I 247

564.7 565.2 4.4 I 248

558.6 559.2 1.11 QC- ACN- AA-XB 249

609.8 610.3 5.63 I 250

602.7 603.1 1.03 QC- ACN- TFA-XB 251

596.7 597.3 1.37 QC- ACN- AA-XB 252

569.7 570.1 1.12 QC- ACN- AA-XB 253

554.6 555.3 1.35 QC- ACN- AA-XB 254

595.7 596.3 1.14 QC- ACN- AA-XB 255

542.6 543.4 1.29 QC- ACN- AA-XB 256

512.6 513.4 1.06 QC- ACN- TFA-XB 257

457.5 458.2 1.31 QC- ACN- AA-XB 258

471.6 472.2 1.41 QC- ACN- AA-XB 259

556.7 557.1 1.77 QC- ACN- AA-XB 260

456.5 457.3 1.07 QC- ACN- AA-XB 261

498.6 499.1 1.24 QC- ACN- AA-XB 262

512.6 513.3 1.06 QC- ACN- TFA-XB 263

528.6 529.3 1.32 QC- ACN- AA-XB 264

523.6 524.2 1.3 QC- ACN- AA-XB 265

534.6 535.4 1.07 QC- ACN- TFA-XB 266

514.6 515.4 1.42 QC- ACN- AA-XB 267

485.6 486.5 0.73 A 268

540.6 541.2 1.36 QC- ACN- AA-XB 269

583.7 584.2 1.26 QC- ACN- AA-XB 270

484.6 485.1 1.38 QC- ACN- AA-XB 271

528.6 529.4 1.38 QC- ACN- AA-XB 272

498.6 499.4 1.44 QC- ACN- AA-XB 273

588.7 589.1 1.33 QC- ACN- AA-XB 274

579.7 580.2 0.86 QC- ACN- TFA-XB 275

568.7 569.3 1.64 QC- ACN- AA-XB 276

498.6 499.3 1.45 QC- ACN- AA-XB 277

516.6 517.2 1.6 QC- ACN- AA-XB 278

514.6 515.2 1.23 QC- ACN- AA-XB 279

484.6 485.2 1.3 QC- ACN- AA-XB 280

520.6 521.2 1.18 QC- ACN- TFA-XB 281

542.6 543.3 1.81 QC- ACN- AA-XB 282

442.5 443.2 0.98 QC- ACN- TFA-XB 283

514.6 515.3 1.39 QC- ACN- AA-XB 284

509.6 510.2 1.33 QC- ACN- AA-XB 285

497.6 498.3 1.36 QC- ACN- AA-XB 286

567.7 568.5 1.58 QC- ACN- AA-XB 287

593.7 594.3 0.91 QC- ACN- TFA-XB 288

579.7 580.3 0.9 QC- ACN- TFA-XB 289

560.7 561.2 1.56 QC- ACN- TFA-XB 290

556.6 557.2 1.25 QC- ACN- TFA-XB 291

512.6 513.3 1.56 QC- ACN- AA-XB 292

526.6 527.2 1.67 QC- ACN- AA-XB 293

595.7 596.3 1.36 QC- ACN- AA-XB 294

567.7 568.4 1.18 QC- ACN- AA-XB 295

581.7 582.4 1.45 QC- ACN- AA-XB 296

576.7 577.4 1.77 QC- ACN- AA-XB 297

582.7 583.2 1.42 QC- ACN- AA-XB 298

586.7 587.2 1.92 QC- ACN- AA-XB 299

581.7 582.4 1.17 QC- ACN- AA-XB 300

509.6 510.4 1.37 QC- ACN- AA-XB 301

567.7 568.4 1.14 QC- ACN- AA-XB 302

554.6 555.4 1.41 QC- ACN- AA-XB 303

512.6 513.3 1.57 QC- ACN- AA-XB 304

555.6 556.3 1.21 QC- ACN- AA-XB 305

540.7 541.4 1.84 QC- ACN- AA-XB 306

568.7 569.4 1.35 QC- ACN- AA-XB 307

595.7 596.4 1.06 QC- ACN- TFA-XB 308

614.7 615.4 2.06 QC- ACN- AA-XB 309

526.6 527.2 1.55 QC- ACN- TFA-XB 310

526.6 527.2 1.7 QC- ACN- AA-XB 311

541.6 542.1 1.16 QC- ACN- AA-XB 312

553.6 554.4 1.18 QC- ACN- AA-XB 313

510.6 511.3 1.46 QC- ACN- AA-XB 314

526.6 527.2 1.72 QC- ACN- AA-XB 315

581.7 582.2 1.1 QC- ACN- AA-XB 316

540.7 541.4 1.57 QC- ACN- TFA-XB 317

555.7 556.2 1.11 QC- ACN- AA-XB 318

635.8 318.8 1.14 QC- ACN- TFA-XB 319

623.8 312.8 1.13 QC- ACN- TFA-XB 320

538.6 539.3 1.76 QC- ACN- AA-XB 321

583.7 584.3 1.33 QC- ACN- AA-XB 322

596.7 597.2 0.96 QC- ACN- TFA-XB 323

581.7 582.4 1.37 QC- ACN- AA-XB 324

595.7 596.2 1.16 QC- ACN- TFA-XB 325

596.7 597.1 1.75 QC- ACN- AA-XB 326

567.7 568.4 1.02 QC- ACN- TFA-XB 327

579.7 580.4 1.05 QC- ACN- TFA-XB 328

524.6 525.3 1.59 QC- ACN- AA-XB 329

581.7 582.4 1.07 QC- ACN- TFA-XB 330

581.7 582.2 1.09 QC- ACN- TFA-XB 331

567.6 568.2 1.32 QC- ACN- AA-XB 332

611.7 612.4 1.24 QC- ACN- AA-XB 333

611.7 612.4 2.18 QC- ACN- AA-XB 334

553.7 554.3 1.39 QC- ACN- AA-XB 335

583.7 584.4 1.08 QC- ACN- TFA-XB 336

567.6 568.3 1.11 QC- ACN- TFA-XB 337

567.7 568.3 1.04 QC- ACN- TFA-XB 338

593.7 594.4 1.16 QC- ACN- AA-XB 339

583.7 584.4 1.09 QC- ACN- TFA-XB 340

581.7 582.4 1.18 QC- ACN- AA-XB 341

638.8 639.5 0.97 QC- ACN- TFA-XB 342

666.8 667.3 1.16 QC- ACN- AA-XB 343

609.8 610.1 1.07 QC- ACN- TFA-XB 344

607.8 608.4 1.32 QC- ACN- AA-XB 345

540.6 541.3 1.29 QC- ACN- AA-XB 346

540.6 541.4 1.35 QC- ACN- AA-XB 347

599.7 600.4 1.06 QC- ACN- TFA-XB 348

638.8 639.3 1.17 QC- ACN- AA-XB 349

595.7 596.4 1.29 QC- ACN- AA-XB 350

607.8 608.2 1.19 QC- ACN- AA-XB 351

621.8 622.4 1.08 QC- ACN- TFA-XB 352

569.7 570.1 1.06 QC- ACN- TFA-XB 353

596.7 597.2 1.34 QC- ACN- TFA-XB 354

595.7 596.2 1.25 QC- ACN- AA-XB 355

595.7 596.3 1.14 QC- ACN- TFA-XB 356

554.6 555.2 1.51 QC- ACN- AA-XB 357

569.7 570.3 1.25 QC- ACN- AA-XB 358

524.6 525.4 1.28 QC- ACN- TFA-XB 359

680.8 681.4 1.22 QC- ACN- AA-XB 360

512.6 513.2 1.59 QC- ACN- AA-XB 361

621.8 622.3 1.32 QC- ACN- AA-XB 362

582.7 583.3 1.44 QC- ACN- TFA-XB 363

567.6 568.2 1.28 QC- ACN- AA-XB 364

526.6 527.3 1.73 QC- ACN- AA-XB 365

609.8 610.4 1.02 QC- ACN- TFA-XB 366

542.6 543.4 1.58 QC- ACN- AA-XB 367

512.6 513.2 1.28 QC- ACN- TFA-XB 368

581.7 582.3 1.17 QC- ACN- AA-XB 369

595.7 596.2 1.08 QC- ACN- TFA-XB 370

526.6 527.2 1.4 QC- ACN- TFA-XB 371

649.8 650.4 1.26 QC- ACN- AA-XB 372

602.7 603.2 1.23 QC- ACN- TFA-XB 373

445.5 446.4 1.19 QC- ACN- AA-XB 374

415.5 416.4 0.82 QC- ACN- TFA-XB 375

498.6 499.4 0.65 QC- ACN- TFA-XB 376

440.5 441.2 1.01 QC- ACN- AA-XB 377

496.6 497.3 0.74 QC- ACN- AA-XB 378

481.6 482.2 0.79 QC- ACN- AA-XB 379

538.6 539.1 1.07 QC- ACN- TFA-XB 380

556.6 557.1 1.57 QC- ACN- AA-XB 381

511.6 512.2 1.36 QC- ACN- AA-XB 382

614.7 615.1 1.34 QC- ACN- AA-XB 383

612.7 613.2 1.25 QC- ACN- AA-XB 384

522.6 523.3 1.3 QC- ACN- AA-XB 385

484.6 485.2 1.34 QC- ACN- AA-XB 386

470.5 471.1 0.91 QC- ACN- TFA-XB 387

538.6 539.3 1.25 QC- ACN- AA-XB 388

596.7 597.2 1.33 QC- ACN- TFA-XB 389

496.6 497.2 1.08 QC- ACN- AA-XB 390

574.7 575.1 1.35 QC- ACN- AA-XB 391

554.6 555.0 1.17 QC- ACN- TFA-XB 392

495.6 496.2 1.26 QC- ACN- AA-XB 393

481.6 482.0 1.18 QC- ACN- AA-XB 394

485.6 486.1 1.75 QC- ACN- AA-XB 395

586.7 587.0 1.48 QC- ACN- AA-XB 396

535.6 536.1 1.73 QC- ACN- AA-XB 397

606.8 607.3 1.12 QC- ACN- AA-XB 398

551.6 552.1 1.28 QC- ACN- AA-XB 399

566.7 567.4 0.64 QC- ACN- TFA-XB 400

565.7 566.2 1.31 QC- ACN- AA-XB 401

509.6 510.3 1.35 QC- ACN- AA-XB 402

614.7 615.1 1.2 QC- ACN- TFA-XB 403

521.6 522.3 1.55 QC- ACN- AA-XB 404

495.6 496.1 1.39 QC- ACN- AA-XB 405

578.7 579.2 1.27 QC- ACN- AA-XB 406

410.5 411.3 1.39 QC- ACN- AA-XB 407

507.6 508.2 1.29 QC- ACN- TFA-XB 408

511.6 512.1 1.27 QC- ACN- AA-XB

Example 409N-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyridazin-3-yl)cyclopropanecarboxamide

Step 1

A mixture of 4,6-dichloro-3-methylpyridazine (112 mg, 0.687 mmol),cyclopropanecarboxamide (64.3 mg, 0.756 mmol), Cs₂CO₃ (448 mg, 1.374mmol), xantphos (59.6 mg, 0.103 mmol) and Pd₂(dba)₃ (62.9 mg, 0.069mmol) in 1,4-Dioxane (1 mL) was placed in a microwave vessel, spargedwith N₂ for 5 minutes, sealed, and heated at 130° C. for 20 minutes.Cooled and filtered then purified by HPLC. HPLC conditions: PhenomenexLuna 5 micron C18 column (30×100 mm); MeCN (0.1% TFA)/water (0.1% TFA);10%-100% gradient over 15 minutes; 30 mL/min. Isolated product fractionsand diluted with AcOEt (50 mL), which was washed with sat NaHCO₃ (30mL), dried over MgSO₄ and concentrated under vacuo to giveN-(5-chloro-6-methylpyridazin-3-yl)cyclopropanecarboxamide (35 mg, 0.165mmol, 24.07% yield). LCMS m/z 211.9/213.9 (M+H)⁺; HPLC t_(R) 0.72 min(analytical HPLC Method A); ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.74-9.46(m, 1H), 8.60 (s, 1H), 2.72 (s, 3H), 1.95 (tt, J=7.9, 4.6 Hz, 1H),1.22-1.10 (m, 2H), 1.03-0.92 (m, 2H).

Step 2

A mixture of N-(5-chloro-6-methylpyridazin-3-yl)cyclopropanecarboxamide(10 mg, 0.047 mmol), 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline(19.30 mg, 0.094 mmol), Pd₂(dba)₃ (4.33 mg, 4.72 μmol), xantphos (5.47mg, 9.45 μmol) and Cs₂CO₃ (46.2 mg, 0.142 mmol) in 1,4-Dioxane (1 mL)was sparged with N₂ for 5 minutes. The reaction vessel was sealed andheated to 130° C. in a microwave for 30 min. Cooled and filtered thenpurified by HPLC to giveN-(5-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-6-methylpyridazin-3-yl)cyclopropanecarboxamide(2.5 mg, 6.52 μmol, 13.81% yield). LCMS m/z 380.2 (M+H)⁺; HPLC t_(R)1.00 min (analytical HPLC Method QC-ACN-AA-XB); ¹H NMR (500 MHz,DMSO-d₆) δ 10.85 (s, 1H), 8.54 (s, 1H), 7.90 (s, 1H), 7.73 (d, J=6.7 Hz,1H), 7.37-7.31 (m, 2H), 7.29-7.23 (m, 1H), 3.93 (s, 3H), 2.56 (d, J=3.1Hz, 6H), 1.93 (br. s., 1H), 0.80-0.61 (m, 4H)

Example 4106-(cyclopropanecarboxamido)-4-((3-(5-(2-(dimethylamino)-2-oxoethyl)oxazol-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

To a mixture of3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxybenzoicacid (ref: Wipf, P. et al.; Org. Lett., 2004, vol. 6, #20, p. 3593-3595(98 mg, 0.288 mmol) in dichloromethane (5 mL) and THE (5 mL) was addedoxalyl chloride (0.050 mL, 0.577 mmol) and 1 drop of DMF. Stirred forone hour. Reaction mixture was concentrated in vacuo then dissolved inTHE (5 mL). Ethyl 4-(bis(trimethylsilyl)amino)but-2-ynoate (102 mg,0.375 mmol) and TBAF (0.288 mL, 0.288 mmol) were added. Stirred at rtovernight then quenched with water. The reaction mixture was dilutedwith ethyl acetate and washed with sat NaCl. The organic layer was driedwith MgSO₄, filtered and concentrated. The crude material was purifiedon a silica gel cartridge (24 g) using an EtOAc/Hex gradient (0-100%EtOAc over 13 CV) to give ethyl4-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxybenzamido)but-2-ynoate(55 mg, 0.123 mmol, 42.5% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 11.10(s, 1H), 8.28 (br s, 1H), 8.08-7.84 (m, 2H), 7.52 (dd, J=7.9, 1.5 Hz,1H), 7.35 (t, J=7.9 Hz, 1H), 7.02 (s, 1H), 4.46 (d, J=5.3 Hz, 2H), 4.26(d, J=7.3 Hz, 2H), 3.86 (s, 3H), 1.69 (br s, 3H), 1.33 (t, J=7.0 Hz, 3H)

Step 2

To a mixture of ethyl4-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxybenzamido)but-2-ynoate(55 mg, 0.123 mmol) in CH₂Cl₂ (5 mL) was added silica. The reaction wasstirred at rt for 5 days. Reaction mixture was filtered washing wellwith 5% MeOH/DCM. Filtrate was concentrated. The crude material waspurified on a silica gel cartridge (12 g) using an EtOAc/Hex gradient(0-100% EtOAc over 20 CV) to give ethyl2-(2-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate(40 mg, 0.089 mmol, 72.7% yield). LCMS m/z 449.1 (M+H)⁺; HPLC t_(R) 0.84min (analytical HPLC Method B).

Step 3

A mixture of ethyl2-(2-(3-((6-chloro-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate(40 mg, 0.089 mmol), cyclopropanecarboxamide (7.58 mg, 0.089 mmol),cesium carbonate (58.1 mg, 0.178 mmol), xantphos (7.73 mg, 0.013 mmol)and Pd₂(dba)₃ (8.16 mg, 8.91 μmol) in 1,4-Dioxane (2 mL) was placed in amicrowave vessel, sparged with N₂ for 5 minutes, sealed, and heated at130° C. for 20 minutes. After cooling the reaction mixture was dilutedwith ethyl acetate and washed with sat NaCl. The organic layer was driedwith MgSO₄, filtered and concentrated. The crude material was purifiedon a silica gel cartridge (12 g) using an EtOAc/Hex gradient (0-100%EtOAc over 21 CV then held at 100% for 9CV) to give ethyl2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate(31 mg, 0.062 mmol, 69.9% yield). To a mixture of ethyl2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)acetate(31 mg, 0.062 mmol) in THE was added 1N NaOH (1 mL). Stirred at rt for 2hours. The reaction mixture was diluted with ethyl acetate and washedwith sat KH₂PO₄. The organic layer was dried with MgSO₄, filtered andconcentrated to afford2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)aceticacid (24 mg, 0.051 mmol, 84% yield). LCMS m/z 470.21 (M+H)⁺; HPLC t_(R)0.69 min (analytical HPLC Method B).

Step 4

To a mixture of2-(2-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)oxazol-5-yl)aceticacid (24 mg, 0.051 mmol, 84%), dimethylamine hydrochloride (6.95 mg,0.085 mmol), and BOP (11.31 mg, 0.026 mmol) in DMF (1 mL) was added Et₃N(0.012 mL, 0.085 mmol). Stirred at rt for 1 hour. Filtered and purifiedby HPLC to give6-(cyclopropanecarboxamido)-4-((3-(5-(2-(dimethylamino)-2-oxoethyl)oxazol-2-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(3.7 mg, 7.30 μmol, 42.9% yield). LCMS m/z 497.2 (M+H)⁺; HPLC t_(R) 1.25min (analytical HPLC Method QC-ACN-AA-XB); 1H NMR in DMSO-d6 isconsistent with desired product (500 MHz, DMSO-d6) δ 11.34 (s, 1H),11.02 (s, 1H), 9.14 (s, 1H), 8.15 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.60(d, J=7.8 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.18 (s, 1H), 3.97 (s, 2H),3.73 (s, 3H), 3.08 (s, 3H), 2.86 (s, 3H), 2.07 (t, J=5.2 Hz, 1H),0.92-0.72 (m, 4H).

The Examples in Table 5 were prepared using a similar procedure used toprepare Example 410.

TABLE 5 Obs. Ex. MS QC No. Structure MW Ion RT Method 411

526.6 527.4 0.95 QC- ACN- TFA-XB 412

579.7 580.2 1.04 QC- ACN- AA-XB 413

465.5 466.4 1.14 QC- ACN- AA-XB 414

507.5 508.4 1.15 QC- ACN- AA-XB 415

548.6 549.2 1.13 QC- ACN- AA-XB 416

549.6 550.1 1.05 QC- ACN- TFA-XB 417

598.6 599.4 1.25 QC- ACN- AA-XB 418

535.6 536.1 0.99 QC- ACN- TFA-XB 419

521.5 522.2 1.11 QC- ACN- AA-XB 420

511.5 512.1 0.98 QC- ACN- AA-XB 421

562.0 562.3 1.45 QC- ACN- TFA-XB

Example 4226-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

To a solution of 2-bromo-6-nitrophenol (5 g, 22.94 mmol) in DMF (18 ml)was added potassium carbonate (9.51 g, 68.8 mmol). The resulting mixturewas stirred for 15 minutes, then iodomethane (2.87 ml, 45.9 mmol) wasadded. The resulting mixture was stirred at room temperature overnight.

HPLC and LC-MS indicated complete conversion to product. Cold water wasadded (75 mL), and the resulting mixture was stirred and sonicated.Next, the solid was collected with filtration. This material was thendissolved in EtOAc (150 mL). This solution was washed 1× with 10% LiCland 1× with brine. The reaction mixture was dried over sodium sulfate,then filtered and concentrated. This was loaded onto a 120 g ISCOcolumn, then purified by flash chromatography eluting with 0-50% EtOAcin hexanes. The reaction afforded a pale yellow solid,1-bromo-2-methoxy-3-nitrobenzene (4.997 g, 20.46 mmol, 89% yield) HPLCt_(R) 0.92 min (analytical HPLC Method A).

Step 2

A mixture of 1-bromo-2-methoxy-3-nitrobenzene (2.48 g, 9.62 mmol), zinc(6.29 g, 96 mmol) and ammonium chloride (5.15 g, 96 mmol) in ethanol (40mL) and water (5.71 mL) was stirred at room temperature overnight. Thereaction was then diluted with dichloromethane (200 ml), and filtered.The filtrate was washed with water (50 ml), dried (Na₂SO₄), andconcentrated. Redissolved this material in DCM, and loaded onto a 80 gcolumn for purification by flash chromatography, eluting with 0-100%EtOAc in hexanes. The reaction afforded 3-bromo-2-methoxyaniline (1.95g, 9.17 mmol, 95% yield) as a colorless oil.

HPLC t_(R) 0.77 min (analytical HPLC Method A).

Step 3

A mixture of 3-bromo-2-methoxyaniline (1.0 g, 4.95 mmol),Bis(triphenylphosphine)palladium(II) chloride (0.347 g, 0.495 mmol), andCopper(I) iodide (0.377 g, 1.980 mmol) in DMA (20 mL) was stirred atroom temperature and degassed by bubbling dry nitrogen through it for 10minutes. Then ethynyltrimethylsilane (3.50 mL, 24.75 mmol) anddiisopropylamine (15.41 mL, 109 mmol) were added and the reactionmixture immediately became a yellow solution. The pressure vessel wasthen sealed and placed into a warm 105° C. bath. Stirred at 105° C.overnight.

The diisopropylamine was evaporated and the excess TMS-acetylene, thendiluted with 100 mL ethyl acetate. The organic solution was washed with1×1:1 ammonium hydroxide:sat. ammonium chloride, 1× sat. ammoniumchloride, 1×10% aq. LiCl, 1× brine and dried over sodium sulfate. Thiswas then filtered and concentrated, and loaded onto a 80 g ISCO columnfor purification by flash chromatography eluting with 0-100% EtOAc inhexanes to afforded 2-methoxy-3-((trimethylsilyl)ethynyl)aniline (995mg, 2.95 mmol, 59.6% yield) as an impure brown solid. Carried on as-isto deprotection. LCMS m/z 220.2 (M+H)⁺; HPLC t_(R) 0.94 min (analyticalHPLC Method A).

Step 4

A mixture of 2-methoxy-3-((trimethylsilyl)ethynyl)aniline (995 mg, 4.54mmol) and potassium carbonate (1881 mg, 13.61 mmol) in methanol (15 mL)was stirred at room temperature for 30 minutes. After 30 minutes, thereaction was complete. Partitioned between EtOAc (50 mL) and water (25mL). The aqueous layer was washed with 1× EtOAc, then washed combinedEtOAc layer 1× saturated ammonium chloride, 1× brine. The reactionmixture was dried over sodium sulfate, then filtered and concentrated.The oil was loaded onto a 12 g ISCO column, then purified by flashchromatography, eluting with 0-10% MeOH in DCM to afford3-ethynyl-2-methoxyaniline (301 mg, 2.004 mmol, 44.2% yield) as anorange oil. HPLC t_(R) 0.52 min (analytical HPLC Method A).

Step 5

4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (220 mg, 1.052 mmol)was dissolved in Tetrahydrofuran (6 mL) and 3-ethynyl-2-methoxyaniline(163 mg, 1.105 mmol) was added. To this solution was added lithiumbis(trimethylsilyl)amide (2.63 mL, 2.63 mmol) in a dropwise manner (<2min) using a needle and syringe and the reaction stirred until completeby LCMS (˜15 min). HCl (1M aq) (1.579 mL, 1.579 mmol) was added toquench the residual base. Then the reaction was partitioned betweenEtOAc and water. The water layer was washed 1× ethyl acetate, and thenthe combined organic layer was washed 1× ammonium chloride (sat.), 1×brine. It was then dried over sodium sulfate, then filtered andconcentrated to afford the crude acetylene as a tan solid. The reactionmixture was redissolved in DCM, then loaded onto a 24 g ISCO column forpurification by flash chromatography eluting with 0-100% EtOAc inhexanes. The reaction afforded6-chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(228 mg, 0.677 mmol, 64.4% yield) as a white solid. LCMS m/z 320.2(M+H)⁺; HPLC t_(R) 0.90 min (analytical HPLC Method A).

Step 6

Benzoic acid (2 mg, 0.016 mmol), L-Ascorbic acid sodium salt (2 mg,10.10 μmol), and Copper(II) sulfate (2 mg, 0.013 mmol) were all weighedinto the small flask containing6-chloro-4-((3-ethynyl-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide(77 mg, 0.241 mmol). A solution of 4-(2-azidoethyl)morpholine (75 mg,0.482 mmol) in t-BuOH (1.5 mL) and Water (1.5 mL) was added and themixture was stirred at room temperature. After stirring overnight, thereaction was complete. Diluted with EtOAc (50 mL) and 10 mL water.Washed organic layer 1× brine, then dried over sodium sulfate, filteredand concentrated. Loaded onto a 12 g column, purified by flashchromatography eluting with 0-100% EtOAc in hexanes. The reactionafforded6-chloro-4-((2-methoxy-3-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(108 mg, 0.216 mmol, 90% yield), a colorless oil. LCMS m/z 476.4 (M+H)⁺;HPLC t_(R) 0.62 min (analytical HPLC Method A).

Step 7

A mixture of6-chloro-4-((2-methoxy-3-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(26 mg, 0.055 mmol), Xantphos (6.32 mg, 10.93 μmol), andcyclopropanecarboxamide (9.30 mg, 0.109 mmol) in dioxane (1 mL) wasdegassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (71.2 mg,0.219 mmol) and Pd₂(dba)₃ (5.00 mg, 5.46 μmol) were added. Then thevessel was sealed, and the reaction was stirred at 120° C. for 2 h. Thereaction was complete by LC-MS. Diluted with DMF, filtered and submittedfor purification. The reaction afforded6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(15.3 mg, 0.029 mmol, 52.3% yield). LCMS m/z 525.5 (M+H)⁺; HPLC t_(R)0.58 min (analytical HPLC Method A); ¹H NMR (500 MHz, DMSO-d₆) δ 11.33(s, 1H), 10.98 (s, 1H), 9.16 (s, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.95(d, J=8.1 Hz, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.34-7.28 (m, 1H), 4.59 (t,J=5.7 Hz, 2H), 3.66 (s, 3H), 3.54 (br. s., 2H), 2.90 (s, 1H), 2.82 (br.s., 1H), 2.74 (s, 1H), 2.46 (br. s., 3H), 2.11-2.04 (m, 1H), 0.85-0.79(m, 4H)

The Examples in Table 6 were prepared using a similar procedure used toprepare Example 422.

TABLE 6 Obs. Ex. MS QC No. Structure MW Ion RT Method 423

526.6 527.2 1.21 QC- ACN- AA-XB 424

548.6 549.4 1.32 QC- ACN- AA-XB 425

591.7 592.3 1.3  QC- ACN- AA-XB

Example 4266-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-(2-((2-methoxyethyl)amino)-2-oxoethyl)-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

A solution of 3-bromo-2-methoxyaniline (0.95 g, 4.70 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.791 g,7.05 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.192 g, 0.235 mmol) and potassiumacetate (1.384 g, 14.11 mmol) in Dioxane (20 mL) in a flask was heatedto reflux overnight. Cooled to room temperature, concentrated in vacuoon Celite. This crude product was purified by flash chromatography usingan ISCO 80 g column (solid loading) eluting with 0-50% EA/hex.Appropriate fractions (25% EtOAc) were collected and concentrated invacuo to give2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.96g, 3.78 mmol, 80% yield) as an off-white solid. LCMS m/z 250.0 (M+H)⁺;HPLC t_(R) 0.70 min (analytical HPLC Method A).

Step 2

To a solution of 1H-1,2,3-triazole (0.524 mL, 9.05 mmol) in water (5 mL)at 50° C. was added bromine (0.625 mL, 12.13 mmol). The reaction wasstirred at 50° C. for 90 minutes, whereupon the precipitated product wasfiltered off. This material was air-dried on the filter. Another aliquotof bromine (0.625 mL, 12.13 mmol) was added to the mother liquor, whichwas stirred at room temperature overnight. After stirring overnight,collected the solid product by filtration. Filtered off a total of4,5-dibromo-1H-1,2,3-triazole (1.83 g, 7.91 mmol, 87% yield) as a whitesolid. Carried on as-is to alkylation.

Step 3

To a solution of 4,5-dibromo-1H-1,2,3-triazole (1.5 g, 6.61 mmol) in DMF(22 mL) at −10° C. (in an salt-ice-water bath) was added first potassiumcarbonate (1.828 g, 13.22 mmol). After stirring 15 minutes, ethylbromoacetate (0.736 mL, 6.61 mmol) was added dropwise. After 1 h, LC-MSindicated that the reaction is complete. The reaction mixture wasquenched with 10 mL water and extracted 4× with 50 mL EtOAc. Thereaction mixture was washed with combined EtOac 1×10% LiCl, 1× brine anddried over sodium sulfate, filtered and concentrated. The reactionmixture was loaded onto a 40 g ISCO column for purification by flashchromatography, eluting with 0-100% EtOAc in hexanes. The reactionafforded ethyl 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)acetate (1.475 g,4.67 mmol, 70.6% yield). Very little of the other isomer observed, noneisolated. LCMS m/z 313.9/315.9 (M+H)⁺; HPLC t_(R) 1.00 min (analyticalHPLC Method A). ¹H NMR (400 MHz, CHLOROFORM-d) δ 5.14 (s, 2H), 4.26 (q,J=7.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 3H)

Step 4

A stirred mixture of ethyl 2-(4,5-dibromo-2H-1,2,3-triazol-2-yl)acetate(1.1 g, 3.51 mmol),2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.876g, 3.51 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.100 g, 0.123 mmol) inDioxane (35 mL) was degassed by bubbling nitrogen through the mixturefor 5 minutes. 2M K₃PO₄ (aq) (5.27 mL, 10.54 mmol) was quickly added andthe reaction mixture heated at 50° C. for 40 minutes. The reactionturned dark almost immediately. LC-MS showed complete consumption of thestarting material. The reaction mixture was cooled to room temperature,then diluted with EtOAc (75 mL). This solution was then dried oversodium sulfate, filtered, concentrated and purified by flashchromatography, eluting with 0-100% EtOAc in hexanes. The reactionafforded ethyl2-(4-(3-amino-2-methoxyphenyl)-5-bromo-2H-1,2,3-triazol-2-yl)acetate(0.595 g, 1.642 mmol, 46.7% yield) as a tan solid. LCMS m/z 355.1/357.1(M+H)⁺; HPLC t_(R) 0.98 min (analytical HPLC Method A).

Step 5

Ethyl2-(4-(3-amino-2-methoxyphenyl)-5-bromo-2H-1,2,3-triazol-2-yl)acetate(0.595 g, 1.675 mmol) was dissolved in Ethanol (12 mL), and 10% Pd on C(0.446 g, 0.419 mmol) was added. This mixture was degassed, and thenflooded with hydrogen gas. This was stirred at 50° C. overnight. Afterstirring overnight, the reaction is complete. Diluted with EtOAc/MeOH,then filtered through Celite and concentrated to afford ethyl2-(4-(3-amino-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate, AcOH(0.575 g, 1.624 mmol, 97% yield) as a tan solid. LCMS m/z 277.1 (M+H)⁺;HPLC t_(R) 0.72 min (analytical HPLC Method A); ¹H NMR (400 MHz,METHANOL-d₄) δ 8.12 (s, 1H), 7.19 (dd, J=7.7, 1.6 Hz, 1H), 6.96 (t,J=7.8 Hz, 1H), 6.84 (dd, J=7.9, 1.6 Hz, 1H), 5.36 (s, 2H), 4.27 (q,J=7.1 Hz, 2H), 3.68 (s, 3H), 1.30 (t, J=7.1 Hz, 3H)

Step 6

To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (155mg, 0.741 mmol) and ethyl2-(4-(3-amino-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate, AcOH (262mg, 0.779 mmol) in Tetrahydrofuran (6 mL) was added lithiumbis(trimethylsilyl)amide (2.224 mL, 2.224 mmol) in a dropwise manner (<1min) using a syringe and the reaction stirred until complete by LCMS(˜15 min). HCl (1M aq) (0.278 mL, 1.112 mmol) was added to quench theresidual base. Then the reaction was partitioned between EtOAc andwater. The water layer was washed 1× ethyl acetate, and then thecombined organic layer was washed 1× ammonium chloride (sat.), 1× brine.It was then dried over sodium sulfate, then filtered and concentrated toafford the crude acetylene as a tan solid. Redissolved in DCM, thenloaded onto a 12 g ISCO column for purification by flash chromatography.Eluted with 0-100% EtOAc in hexanes. The reaction afforded ethyl2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate(135 mg, 0.298 mmol, 40.2% yield) as an off-white solid. LCMS m/z 449.3(M+H)⁺; HPLC t_(R) 0.91 min (analytical HPLC Method A).

Step 7

A mixture of ethyl2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate(120 mg, 0.267 mmol), Xantphos (30.9 mg, 0.053 mmol), andcyclopropanecarboxamide (45.5 mg, 0.535 mmol) in dioxane (3 mL) wasdegassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (348 mg,1.069 mmol) and Pd₂(dba)₃ (24.48 mg, 0.027 mmol) were added, the vesselwas sealed, and the reaction was stirred at 120° C. for 90 minutes. Thereaction was complete by LC-MS, so the crude material was concentratedonto Celite and purified by flash chromatography, using a 24 g ISCOcolumn and eluting with 0-100% EtOAc in hexanes to afford ethyl2-(4-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate(61 mg, 0.120 mmol, 44.9% yield). LCMS m/z 498.4 (M+H)⁺; HPLC t_(R) 0.79min (analytical HPLC Method A).

Step 8

To a solution of ethyl2-(4-(3-((6-(cyclopropanecarboxamido)-3-((methyl-d3)carbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)acetate(61 mg, 0.123 mmol) in Tetrahydrofuran (1 mL) was added 1N NaOH (0.135mL, 0.135 mmol) and a few drops of methanol. The solution was stirred atroom temperature. After 2 h, the reaction is complete. Neutralised with140 uL 1N HCl, then diluted with 50 mL EtOAc. Dried this mixture oversodium sulfate, then filtered and concentrated to afford crude2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)aceticacid (56 mg, 0.113 mmol, 92% yield) as a yellow solid. LCMS m/z 470.2(M+H)⁺; HPLC t_(R) 0.67 min (analytical HPLC Method A).

Step 9

A solution of 2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-2H-1,2,3-triazol-2-yl)aceticacid (30 mg, 0.064 mmol), BOP (42.4 mg, 0.096 mmol), 2-methoxyethanamine(14.40 mg, 0.192 mmol), and DIEA (0.056 mL, 0.320 mmol) in DMF (1 mL)was stirred for 45 minutes at room temperature. The reaction appears tobe complete by LC-MS. The reaction mixture was diluted with DMF, thenfiltered and purified by prep HPLC to afford6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(2-(2-((2-methoxyethyl)amino)-2-oxoethyl)-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(10.6 mg, 0.020 mmol, 30.6% yield) LCMS m/z 527.3 (M+H)⁺; HPLC t_(R)0.67 min (analytical HPLC Method A).

The Examples in Table 7 were prepared using a similar procedure used toprepare Example 426.

TABLE 7 Obs. Ex. MS QC No. Structure MW Ion RT Method 427

496.5 497.3 1.42 QC- ACN- AA-XB 428

552.7 553.2 1.53 QC- ACN- TFA-XB 429

512.5 513.2 0.89 QC- ACN- TFA-XB 430

553.6 554.4 1.6  QC- ACN- AA-XB 431

554.6 555.3 1.77 QC- ACN- AA-XB 432

496.5 497.3 1.27 QC- ACN- AA-XB 433

526.6 527.3 1.14 QC- ACN- TFA-XB 434

532.6 533.3 1.36 QC- ACN- AA-XB 435

521.6 522.3 1.31 QC- ACN- AA-XB 436

531.6 532.24, 1.18 QC- ACN- AA-XB 437

547.6 548.2 1.38 QC- ACN- AA-XB 438

566.6 567.3 1.3  QC- ACN- AA-XB 439

495.6 496.1 1.1  QC- ACN- AA-XB 440

520.6 521.2 1.14 QC- ACN- AA-XB 441

525.6 526.1 1.18 QC- ACN- AA-XB 442

453.5 454.4 0.94 QC- ACN- AA-XB 443

539.6 540.3 1.14 QC- ACN- AA-XB 444

536.6 537.1 1.26 QC- ACN- TFA-XB 445

508.5 509.2 1.16 QC- ACN- AA-XB 446

503.5 504.1 0.84 QC- ACN- TFA-XB 447

512.5 513.2 1.16 QC- ACN- AA-XB 448

454.5 455.2 0.99 QC- ACN- AA-XB 449

538.6 539.2 1.09 QC- ACN- TFA-XB 450

455.5 456.3 1.25 QC- ACN- AA-XB

Example 4514-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-((6-methoxypyridazin-3-yl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

To a solution of 4,5-dibromo-1H-1,2,3-triazole (0.401 g, 1.768 mmol) inDMF (6 mL) at 0° C. (in an ice-water bath) was added first potassiumcarbonate (0.366 g, 2.65 mmol) and then iodomethane (0.116 mL, 1.856mmol) was added dropwise. After stirring 1 h, the reaction appears to beincomplete by HPLC. Added additional 50 uL iodomethane, continuedstirring, now at room temp. Reaction still appears to incomplete. Addedadditional 50 uL iodomethane. Quenched with 10 mL water. Extracted 2×50mL EtOAc. Washed combined EtOac 1×10% LiCl, 1× brine. Then dried oversodium sulfate, filtered and concentrated. Loaded onto a 40 g ISCOcolumn for purification by flash chromatography, eluting with 0-100%EtOAc in hexanes. Two peaks elute, the first eluting being larger by UVabsorbance, but giving no MS signal. This is4,5-dibromo-2-methyl-2H-1,2,3-triazole (0.266 g, 1.082 mmol, 61.2%yield), designated Isomer 2. HPLC t_(R) 0.90 min (analytical HPLC MethodA). ¹H NMR (400 MHz, chloroform-d) δ 4.17 (s, 3H). The second peak issmaller by UV, but gives the correct mass and dibromo isotopic patternin MS. This material is 4,5-dibromo-2-methyl-2H-1,2,3-triazole (0.101 g,1.082 mmol, 61.2% yield) designated Isomer 1. LCMS m/z 242.0/244.0(M+H)⁺; HPLC t_(R) 0.67 min (analytical HPLC Method A). ¹H NMR (400 MHz,chloroform-d) δ 4.08 (s, 3H)

Step 2

A stirred mixture of 4,5-dibromo-2-methyl-2H-1,2,3-triazole (100 mg,0.415 mmol),2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (98 mg,0.394 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (16.95 mg, 0.021 mmol) inDioxane (3 mL) was degassed by bubbling nitrogen through the mixture for5 minutes. 2M K₃PO₄ (aq) (0.623 mL, 1.245 mmol) was quickly added andthe reaction mixture heated at 50° C. for 40 minutes. The reactionturned dark almost immediately even at this lower temperature. LC-MSshowed complete consumption of the starting material. The reactionmixture was cooled to room temperature, then diluted with EtOAc (75 mL).This solution was then dried over sodium sulfate, filtered, concentratedand purified by flash chromatography, eluting with 0-100% EtOAc inhexanes. The reaction afforded3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (70 mg,0.247 mmol, 59.6% yield) as a yellow oil. LCMS m/z 283.1/285.1 (M+H)⁺;HPLC t_(R) 1.11 min (analytical HPLC Method A).

Step 3

3-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2-methoxyaniline (0.145 g,0.512 mmol) was dissolved in Ethyl acetate (5 mL), and 10% Pd on C(0.136 g, 0.128 mmol) was added. This mixture was degassed, and thenflooded with hydrogen gas. This was stirred overnight at roomtemperature. After stirring overnight, LC-Ms indicates a clean reactionwith ˜30% conversion to desired product. Added additional 10% Pd on C(0.136 g, 0.128 mmol) and Ethanol (1 mL). This mixture was re-degassed,and then flooded with hydrogen gas. This was stirred at 50° C. for 3 h.After 3 h, the reaction is complete. Filtered and concentrated to afford2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline (78 mg, 0.374 mmol,73.1% yield) as a tan solid. LCMS m/z 205.1 (M+H)⁺; HPLC t_(R) 0.70 min(analytical HPLC Method A).

Step 4

To a solution of 4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide (270mg, 1.292 mmol) and 2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)aniline(290 mg, 1.421 mmol) in Tetrahydrofuran (10 mL) was added lithiumbis(trimethylsilyl)amide (3.23 mL, 3.23 mmol) in a dropwise manner (<5min) using a syringe and the reaction stirred until complete by LCMS(˜15 min). HCl (1M aq) (0.484 mL, 1.937 mmol) was added to quench theresidual base. Then the reaction was partitioned between EtOAc andwater. The water layer was washed 1× ethyl acetate, and then thecombined organic layer was washed 1× ammonium chloride (sat.), 1× brine.It was then dried over sodium sulfate, then filtered and concentrated toafford the crude acetylene as a tan solid. Redissolved in DCM, thenloaded onto a 24 g ISCO column for purification by flash chromatography.Eluted with 0-100% EtOAc in hexanes. The reaction afforded6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(182 mg, 0.473 mmol, 36.6% yield) as an off-white solid. LCMS m/z 377.2(M+H)⁺; HPLC t_(R) 0.87 min (analytical HPLC Method A).

Step 5

A mixture of6-chloro-4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(30 mg, 0.080 mmol), Xantphos (9.21 mg, 0.016 mmol), and6-methoxypyridazin-3-amine (19.92 mg, 0.159 mmol) in dioxane (1.5 mL)was degassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (104mg, 0.318 mmol) and Pd₂(dba)₃ (7.29 mg, 7.96 μmol) were added, thevessel was sealed, and the reaction was stirred at 130° C. for 45minutes. The reaction was complete by LC-MS. The reaction was cooled toroom temperature, and then was diluted with DMF. This solution was thenfiltered and purified by prep HPLC. The reaction afforded4-((2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-6-((6-methoxypyridazin-3-yl)amino)-N-trideuteromethylpyridazine-3-carboxamide(22 mg, 0.046 mmol, 58.2% yield) as a yellow solid. LCMS m/z 466.2(M+H)⁺; HPLC t_(R) 0.69 min (analytical HPLC Method A);

¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.27 (s, 1H), 9.14 (s, 1H),8.16 (s, 1H), 7.96 (s, 1H), 7.93 (d, J=9.5 Hz, 1H), 7.68 (dd, J=7.9, 1.5Hz, 1H), 7.57 (dd, J=8.0, 1.4 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.22 (d,J=9.5 Hz, 1H), 4.24 (s, 3H), 3.95 (s, 3H), 3.68 (s, 3H)

The Examples in Table 8 were prepared using a similar procedure used toprepare Example 451.

TABLE 8 Obs. Ex. MS QC No. Structure MW Ion RT Method 452

482.5 483.2 1.57 QC- ACN- AA-XB 453

442.5 443.2 1.57 QC- ACN- AA-XB 454

509.6 510.1 1.59 QC- ACN- AA-XB

Example 4556-(cyclopropanecarboxamido)-4-((3-(5-(1,1-dioxidothiomorpholine-4-carbonyl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

A stirred mixture of methyl 3-chloro-1-methyl-1H-pyrazole-5-carboxylate(200 mg, 1.146 mmol),2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (499mg, 2.005 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladiumdichloride (37.3 mg, 0.057 mmol) in Dioxane (6 ml) was degassed bybubbling nitrogen through the mixture for 5 minutes. 2M K₃PO₄ (aq)(1.718 ml, 3.44 mmol) was quickly added and the reaction mixture heatedat 125° C. for 1 hr. The reaction mixture was partitioned between EtOAc(30 ml) and water (30 ml). The organic layer was washed with brine (30ml), dried (Na₂SO₄) and concentrated to afford a brown oil that waschromatographed on a 24 gm ISCO silica gel cartridge, eluting with a0-50% EtOAc/Hexanes gradient. The pure fractions were concentrated toafford methyl3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate (89 mg,0.337 mmol, 29.4% yield) as a tan solid. LCMS m/z 262.2 (M+H)⁺; HPLCt_(R) 0.65 min (analytical HPLC Method A).

Step 2

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(72 mg, 0.344 mmol) and methyl3-(3-amino-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate (90 mg,0.344 mmol) in Tetrahydrofuran (3 mL) at rt was added dropwise over 5minutes LiHMDS, 1M (0.861 mL, 0.861 mmol). The resulting solution wasstirred at rt for 30 minutes. The reaction mixture was quenched with 1ml of saturated NH₄Cl solution. The resulting mixture was partitionedbetween EtOAc (30 ml) and saturated NH₄Cl solution (30 ml). The organiclayer was washed with brine (30 ml), dried (Na₂SO₄) and concentrated toan amber oil that was chromatographed on a 12 gm ISCO silica gelcartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractionswere concentrated to afford methyl3-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate(79 mg, 0.178 mmol, 51.8% yield) as a tan solid. LCMS m/z 434.2 (M+H)⁺;HPLC t_(R) 0.97 min (analytical HPLC Method A).

Step 3

A mixture of3-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate(0.141 g, 0.325 mmol), Xantphos (0.038 g, 0.065 mmol), andcyclopropanecarboxamide (0.055 g, 0.650 mmol) in dioxane (3 mL) wasdegassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (0.424 g,1.300 mmol) and Pd₂(dba)₃ (0.030 g, 0.032 mmol) were added, the vesselwas sealed, and the reaction was stirred at 130° C. for 45 minutes. Thereaction was complete by LC-MS. The reaction was cooled to roomtemperature, then concentrated and loaded directly onto a 12 g ISCOcolumn for purification by flash chromatography, eluting with 0-15% MeOHin DCM to afford methyl3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate(99 mg, 0.203 mmol, 62.5% yield) as a pale yellow solid. LCMS m/z 483.5(M+H)⁺; HPLC t_(R) 0.80 min (analytical HPLC Method A). ¹H NMR (400 MHz,DMSO-d₆) δ 11.32 (s, 1H), 10.96 (s, 1H), 9.14 (s, 1H), 8.13 (s, 1H),7.71 (dd, J=7.9, 1.6 Hz, 1H), 7.44 (dd, J=7.9, 1.5 Hz, 1H), 7.30-7.24(m, 2H), 4.18 (s, 3H), 3.88 (s, 3H), 3.64-3.60 (m, 3H), 2.13-2.04 (m,1H), 0.86-0.79 (m, 4H)

Step 4

A mixture of methyl3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate(99 mg, 0.205 mmol) and lithium hydroxide monohydrate (10.34 mg, 0.246mmol) in THE (2 mL) and Water (0.4 mL) was stirred at rt for 24 hr. Thevolatiles were removed in vacuo to afford3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylicacid, lithium salt (96 mg, 0.192 mmol, 93% yield) as a yellow solid.Used as is. LCMS m/z 469.4 (M+H)⁺; HPLC t_(R) 0.70 min (analytical HPLCMethod A).

Step 5

A mixture of3-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylicacid, lithium salt (10 mg, 0.021 mmol), thiomorpholine 1,1-dioxide (7.11mg, 0.053 mmol), BOP (12.09 mg, 0.027 mmol) and Et₃N (0.015 mL, 0.105mmol) in DMF (0.2 mL) was agitated at rt for 1 h. The reaction wascomplete by LC-MS, so the reaction was diluted to 1.5 mL with methanol,then filtered and submitted for purification. The reaction afforded6-(cyclopropanecarboxamido)-4-((3-(5-(1,1-dioxidothiomorpholine-4-carbonyl)-1-methyl-1H-pyrazol-3-yl)-2-methoxyphenyl)amino)-N-trideuteromethylpyridazine-3-carboxamide(8.1 mg, 0.013 mmol, 60.5% yield) LCMS m/z 586.4 (M+H)⁺; HPLC t_(R) 0.68min (analytical HPLC Method A).

¹H NM/R (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 11.03 (s, 1H), 9.15 (s, 1H),8.18 (s, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.26 (t,J=7.7 Hz, 1H), 7.05 (s, 1H), 4.01 (br. s., 5H), 3.95 (s, 3H), 3.63 (s,3H), 3.34 (br. s., 2H), 2.12-2.04 (m, 2H), 0.91-0.77 (m, 4H)

The Examples in Table 9 were prepared using a similar procedure used toprepare Example 455.

TABLE 9 Obs. Ex. MS QC No. Structure MW Ion RT Method 456

512.6 513.2 1.35 QC- ACN- AA-XB 457

495.6 496.2 1.49 QC- ACN- AA-XB 458

525.6 526.4 1.43 QC- ACN- AA-XB 459

537.6 538.4 1.35 QC- ACN- AA-XB 460

539.6 540.3 1.41 QC- ACN- AA-XB 461

539.6 540.3 1.36 QC- ACN- AA-XB 462

467.5 468.3 1.34 QC- ACN- AA-XB 463

467.5 468.2 1.28 QC- ACN- AA-XB 464

553.6 554.3 1.69 QC- ACN- AA-XB 465

453.5 454.3 1.21 QC- ACN- AA-XB 466

531.6 532.2 1.24 QC- ACN- AA-XB 467

511.6 512.2 0.92 QC- ACN- TFA-XB 468

495.6 496.4 1.16 QC- ACN- AA-XB 469

525.6 526.2 1.23 QC- ACN- AA-XB 470

520.6 521.4 1.21 QC- ACN- AA-XB 471

525.6 526.4 1.23 QC- ACN- AA-XB 472

524.6 525.0 1.03 QC- ACN- TFA-XB 473

524.6 525.4 1.09 QC- ACN- TFA-XB 474

525.6 526.4 1.1  QC- ACN- AA-XB 475

597.7 598.3 1.63 QC- ACN- AA-XB 476

580.7 581.2 1.26 QC- ACN- AA-XB 477

520.6 521.2 1.4  QC- ACN- AA-XB 478

551.6 552.4 1.2  QC- ACN- AA-XB 479

535.6 536.2 1.57 QC- ACN- AA-XB 480

550.6 551.2 1.32 QC- ACN- AA-XB 481

539.6 540.2 1.44 QC- ACN- AA-XB 482

521.6 522.2 1.51 QC- ACN- AA-XB 483

495.6 496.4 1.32 QC- ACN- AA-XB 484

598.7 599.2 1.29 QC- ACN- AA-XB 485

555.6 556.3 1.46 QC- ACN- AA-XB 486

494.6 495.3 1.21 QC- ACN- AA-XB 487

482.6 483.6 0.74 A 488

584.7 585.1 0.94 QC- ACN- TFA-XB 489

500.6 501.2 1.57 QC- ACN- AA-XB 490

545.6 546.4 1.18 QC- ACN- TFA-XB 491

576.7 577.2 0.86 QC- ACN- TFA-XB 492

536.6 537.2 0.83 QC- ACN- TFA-XB 493

578.6 579.4 1.02 QC- ACN- TFA-XB 494

594.6 595.4 1.42 QC- ACN- AA-XB 495

513.5 514.1 1.49 QC- ACN- AA-XB 496

594.7 595.2 1.32 QC- ACN- AA-XB 497

568.6 569.3 1.44 QC- ACN- AA-XB 498

562.6 563.3 1.14 QC- ACN- TFA-XB 499

583.6 584.3 1.72 QC- ACN- AA-XB 500

499.5 500.4 1.33 QC- ACN- AA-XB 501

535.6 536.2 1.25 QC- ACN- AA-XB 502

614.7 615.2 1.39 QC- ACN- AA-XB 503

603.6 604. 2 1.47 QC- ACN- AA-XB 504

590.7 591.4 0.93 QC- ACN- TFA-XB 505

527.6 528.3 1.62 QC- ACN- AA-XB 506

541.6 542.3 1.53 QC- ACN- TFA-XB 507

569.6 570.1 1.31 QC- ACN- TFA-XB 508

525.6 526.2 1.6  QC- ACN- AA-XB 509

597.7 598.3 1.27 QC- ACN- TFA-XB 510

584.7 585.5 1   QC- ACN- TFA-XB 511

629.7 630.4 1.9  QC- ACN- TFA-XB 512

601.7 602.4 1.78 QC- ACN- TFA-XB 513

555.6 556.2 2.08 QC- ACN- AA-XB 514

570.6 571.4 1.29 QC- ACN- AA-XB 515

596.7 597.3 1.24 QC- ACN- AA-XB 516

622.7 623.5 1.25 QC- ACN- AA-XB 517

582.7 583.3 1.11 QC- ACN- TFA-XB 518

596.7 597.5 1.56 QC- ACN- AA-XB 519

568.6 569.3 1.31 QC- ACN- AA-XB 520

555.6 556.3 1.15 QC- ACN- AA-XB 521

541.6 542.3 1.2  QC- ACN- AA-XB 522

551.6 552.3 1.44 QC- ACN- AA-XB 523

541.6 542.3 0.92 QC- ACN- TFA-XB 524

663.8 664.4 0.79 QC- ACN- TFA-XB 525

565.6 566.3 1.6  QC- ACN- AA-XB 526

552.7 553.4 0.99 QC- ACN- TFA-XB 527

539.6 540.2 1.22 QC- ACN- TFA-XB 528

564.7 565.2 1.21 QC- ACN- AA-XB 529

578.7 579.4 1.16 QC- ACN- AA-XB 530

604.7 605.4 1.19 QC- ACN- AA-XB 531

578.7 579.2 1.49 QC- ACN- AA-XB 532

550.6 551.3 1.19 QC- ACN- AA-XB 533

578.7 579.2 1.24 QC- ACN- AA-XB 534

592.7 593.4 1.26 QC- ACN- AA-XB 535

509.6 510.3 1.64 QC- ACN- AA-XB 536

538.6 539.3 1.21 QC- ACN- AA-XB 537

552.7 553.3 1.19 QC- ACN- AA-XB 538

507.6 508.2 1.26 QC- ACN- TFA-XB 539

509.6 510.3 1.48 QC- ACN- AA-XB 540

569.6 570.2 1.23 QC- ACN- TFA-XB 541

632.8 633.4 1.22 QC- ACN- AA-XB 542

549.6 550.3 0.61 A 543

538.6 539.3 1.39 QC- ACN- AA-XB 544

566.6 567.0 1.61 QC- ACN- AA-XB 545

554.6 555.1 1.24 QC- ACN- TFA-XB 546

526.6 527.2 1.23 QC- ACN- TFA-XB 547

567.6 568.4 1.59 QC- ACN- AA-XB 548

539.6 540.2 1.51 QC- ACN- AA-XB 549

567.6 568.1 1.18 QC- ACN- TFA-XB 550

580.6 581.3 1.54 QC- ACN- AA-XB 551

552.6 553.2 1.43 QC- ACN- AA-XB 552

588.6 589.1 1.25 QC- ACN- TFA-XB 553

525.6 526.3 1.42 QC- ACN- AA-XB 554

553.6 554.1 1.51 QC- ACN- AA-XB 555

537.6 538.3 1.15 QC- ACN- TFA-XB

Example 5564-((3-(1-(2-acetamidoethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

Step 1

A solution of tert-butyl (2-(4-bromo-1H-pyrazol-1-yl)ethyl)carbamate(0.18 g, 0.620 mmol),2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.170g, 0.682 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene palladiumdichloride (0.020 g, 0.031 mmol) was degassed by bubbling N₂ through thesolution for 5 minutes. Then 2M K₃PO₄ (aq) (0.931 mL, 1.861 mmol) wasadded and the mixture was stirred at 100° C. for 1 h. LC-MS showedcomplete conversion to the desired product mass. The reaction mixturewas cooled to room temperature, then diluted with EtOAc (75 mL). Thissolution was then dried over sodium sulfate, filtered, concentrated andpurified by flash chromatography, eluting with 0-100% EtOAc in hexanesto afford tert-butyl(2-(4-(3-amino-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate (177 mg,0.532 mmol, 86% yield) in total, a yellow solid.

LCMS m/z 333.2 (M+H)⁺; HPLC t_(R) 0.68 min (analytical HPLC Method A).

Step 2

To a solution of 4,6-dichloro-N-trideuteromethylpyridazine-3-carboxamide(122 mg, 0.586 mmol) and tert-butyl(2-(4-(3-amino-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate (177 mg,0.532 mmol) in THE (5 mL) was added LiHMDS, 1M in THE (2.130 mL, 2.130mmol) and the reaction stirred at room temperature for a total of 20minutes. The crude reaction was quenched with sat. aqueous ammoniumchloride, then diluted with EtOAc. The aqueous layer was washed 2×EtOAc, and the combined EtOAc layers were washed 1× brine. This solutionwas then dried over sodium sulfate, then filtered and concentrated. Thecrude material was then loaded onto a 24 g ISCO column for purificationby flash chromatography. Eluted with 0-100% EtOAc in hexanes. Thereaction afforded tert-butyl(2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate(184 mg, 0.353 mmol, 66.4% yield) as an off-white solid. LCMS m/z 505.4(M+H)⁺; HPLC t_(R) 0.93 min (analytical HPLC Method A); ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 9.37 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.52(dd, J=7.8, 1.2 Hz, 1H), 7.37 (dd, J=7.9, 1.4 Hz, 1H), 7.25-7.19 (m,1H), 7.17 (s, 1H), 6.95 (t, J=5.6 Hz, 1H), 4.24-4.15 (m, 2H), 3.60 (s,3H), 3.39-3.34 (m, 2H), 1.38-1.33 (m, 9H)

Step 3

A mixture of tert-butyl(2-(4-(3-((6-chloro-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate(182 mg, 0.360 mmol), Xantphos (41.7 mg, 0.072 mmol), andcyclopropanecarboxamide (92 mg, 1.081 mmol) in dioxane (3.5 mL) wasdegassed by bubbling N₂ through it for 5 minutes. Then Cs₂CO₃ (470 mg,1.442 mmol) and Pd₂(dba)₃ (33.0 mg, 0.036 mmol) were added, the vesselwas sealed, and the reaction was stirred at 130° C. for 1 h. Thereaction was complete by LC-MS, so the crude material was concentrateddiluted with EtOAc (75 mL), then dried over sodium sulfate. The reactionmixture was filtered and concentrated, then loaded onto a 24 g ISCOcolumn for purification by flash chromatography, eluting with 0-15% MeOHin DCM to afford tert-butyl(2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate(155 mg, 0.266 mmol, 73.8% yield). LCMS m/z 554.6 (M+H)⁺; HPLC t_(R)0.81 min (analytical HPLC Method A)

Step 4

A solution of tert-butyl(2-(4-(3-((6-(cyclopropanecarboxamido)-3-(trideuteromethylcarbamoyl)pyridazin-4-yl)amino)-2-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)carbamate(155 mg, 0.280 mmol) in DCM (3 mL) and HCl, 4M in 1,4-dioxane (0.700 mL,2.80 mmol) was stirred at room temperature overnight. After stirringovernight, the reaction is complete. Concentrated to a yellow solid,used as-is in the next step.(4-((3-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(125 mg, 0.255 mmol, 91% yield). LCMS m/z 454.3 (M+H)⁺; HPLC t_(R) 0.61min (analytical HPLC Method A).

Step 5

To a solution of4-((3-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(12 mg, 0.026 mmol) in DMF (0.5 mL) and triethylamine (0.011 mL, 0.079mmol) was added acetic anhydride (3.74 μl, 0.040 mmol). The reaction wasstirred at room temperature for 30 minutes, whereupon the reaction wascomplete by LC-MS. Quenched the excess acetic anhydride with methanol,then concentrated to a solid. Redissolved in 2 mL methanol, filtered andsubmitted for purification. The reaction afforded4-((3-(1-(2-acetamidoethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-trideuteromethylpyridazine-3-carboxamide(7.5 mg, 0.015 mmol, 56.6% yield) LCMS m/z 496.2 (M+H)⁺; HPLC t_(R) 0.64min (analytical HPLC Method A); ¹H NM/R (500 MHz, DMSO-d₆) δ 11.33 (s,1H), 10.97 (s, 1H), 9.15 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.02 (t,J=5.4 Hz, 1H), 7.98 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.29 (d, J=7.4 Hz,1H), 7.23-7.17 (m, 1H), 4.22 (t, J=6.1 Hz, 2H), 3.60 (s, 3H), 3.47 (q,J=5.8 Hz, 1H), 2.12-2.04 (m, 2H), 1.80 (s, 3H), 0.88-0.77 (m, 4H)

The Examples in Table 10 were prepared using a similar procedure used toprepare Example 556.

TABLE 10 Obs. Ex. MS QC No. Structure MW Ion RT Method 557

453.5 454.3 0.98 QC- ACN- AA-XB 558

511.6 512.2 1.1 QC- ACN- AA-XB 559

520.6 521.3 1.25 QC- ACN- AA-XB 560

531.6 532.2 1.24 QC- ACN- AA-XB 561

563.6 554.3 1.6 QC- ACN- AA-XB 562

525.6 526.4 1.23 QC- ACN- AA-XB

Example 5634-((3-(1-(2-acetamidoethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)-N-(methyl-d3)pyridazine-3-carboxamide

The Examples in Table 11 were prepared using a similar procedure used toprepare Example 563.

TABLE 11 Obs. Ex. MS QC No. Structure MW Ion RT Method 564

580.6 581.2 1.71 QC- ACN-AA- XB 565

568.6 569.0 1.57 QC- ACN-AA- XB 566

528.6 529.3 1.5 QC- ACN-AA- XB 567

567.6 568.1 1.27 QC- ACN- TFA-XB 568

581.6 582.2 1.82 QC- ACN-AA- XB 569

527.6 528.1 1.24 QC- ACN- TFA-XB 570

568.6 569.2 1.71 QC- ACN-AA- XB 571

595.7 596.2 1.61 QC- ACN-AA- XB 572

580.6 581.2 1.66 QC- ACN-AA- XB 573

612.7 613.3 1.55 QC- ACN-AA- XB 574

545.6 546.1 1.66 QC- ACN-AA- XB 575

585.6 586.1 1.27 QC- ACN- TFA-XB

Example 5766-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)nicotinamide

Step 1

A mixture of tert-butyl 2-methoxy-3-nitrobenzoate (200 mg, 0.790 mmol)and 10% Palladium on carbon (42.0 mg, 0.039 mmol) in ethyl acetate (8ml) was stirred under an atmosphere of hydrogen at rt for 16 hr.Filtration through a 0.45 micron nylon filter and concentration of thefiltrate afforded tert-butyl 3-amino-2-methoxybenzoate (165 mg, 0.739mmol, 94% yield) as a yellow oil. HPLC t_(R) 1.43 min (analytical HPLCMethod A) ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.11 (dd, J=7.7, 1.8 Hz, 1H),6.96-6.89 (m, 1H), 6.88-6.83 (m, 1H), 3.84 (s, 3H), 1.60 (s, 9H).

Step 2

To a heterogeneous, colorless solution of 4,6-dichloronicotinic acid (1g, 5.21 mmol) in Dichloromethane (35 mL) under nitrogen was added oxalyldichloride (0.585 mL, 6.77 mmol), followed by DMF (0.403 mL, 5.21 mmol);effervescence ensued. LCMS after 2 h of mostly homogeneous solutionshowed completion of reaction (quenched with ethanol, see ethyl esterM+H 219.9). The solution was concentrated in vacuo; DCE (20 mL) wasadded, and the solution was concentrated in vacuo. This was repeatedtwice to give crude 4,6-dichloronicotinoyl chloride. Poured 50 mL 28%ammonium hydroxide into a separatory funnel, extracted 3×15 mL DCM.Dried the combined DCM layers over sodium sulfate, then filtered andused this ammonia solution as is in the reaction. This solution wasadded to a homogeneous yellow solution of 4,6-dichloronicotinoylchloride (1.1 g, 5.23 mmol) in 5 mL DCM at 0° C. and TEA (2.186 mL,15.68 mmol). After 15 minutes, the reaction was complete by LC-MS.Diluted with dichloroethane (100 mL) and washed with 1 N aqueous HCl.The layers were separated, and the aqueous layer was extracted withdichloroethane (2×50 mL). The organic layers were combined, dried oversodium sulfate, filtered and concentrated in vacuo. The crude was takenup in DCM, then purified by flash chromatography using an 40 g silicagel column eluting with 0-100% ethyl acetate in hexanes. Appropriatefractions were collected and concentrated in vacuo to give4,6-dichloronicotinamide (0.787 g, 3.91 mmol, 74.9% yield). LCMS m/z190.9 (M+H)⁺; HPLC t_(R) 0.54 min (analytical HPLC Method A). ¹H NMR(400 MHz, DMSO-d₆) δ 8.51-8.49 (m, 1H), 8.11 (br. s., 1H), 7.91-7.87 (m,2H)

Step 3

To a solution of 4,6-dichloronicotinamide (192 mg, 1.008 mmol) andtert-butyl 3-amino-2-methoxybenzoate (225 mg, 1.008 mmol) inTetrahydrofuran (6 mL) at rt was added dropwise over 1 minute LiHMDS, 1M(2.52 mL, 2.52 mmol). The resulting solution was stirred at roomtemperature for 1 hr. The reaction mixture was quenched with 1 ml ofsaturated aqueous ammonium chloride solution. The resulting mixture waspartitioned between EtOAc (30 ml) and saturated NH₄Cl solution (30 ml).The organic layer was washed with brine (30 ml), dried (Na₂SO₄) andconcentrated to an amber oil that was chromatographed on a 12 g silicagel cartridge, eluting with a 0-100% ethyl acetate in hexanes gradient.The pure fractions were concentrated to afford tert-butyl3-((5-carbamoyl-2-chloropyridin-4-yl)amino)-2-methoxybenzoate (106 mg,0.267 mmol, 26.4% yield) as a light yellow solid. LCMS m/z 378.2 (M+H)⁺;HPLC t_(R) 0.91 min (analytical HPLC Method A). ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 9.37 (s, 1H), 7.72 (dd, J=7.9, 1.3 Hz, 1H),7.49 (dd, J=7.8, 1.4 Hz, 1H), 7.27 (t, J=7.9 Hz, 1H), 7.19 (s, 1H), 3.74(s, 3H), 1.56 (s, 9H).

Step 4

A mixture of tert-butyl3-((5-carbamoyl-2-chloropyridin-4-yl)amino)-2-methoxybenzoate (22 mg,0.058 mmol), cyclopropanecarboxamide (49.6 mg, 0.582 mmol), Pd₂(dba)₃,Chloroform adduct (6.02 mg, 5.82 μmol), Xantphos (6.74 mg, 0.012 mmol)and Cs₂CO₃ (76 mg, 0.233 mmol) in Dioxane (1.5 mL) was degassed bybubbling N₂ through the mixture for 5 minutes. The reaction vessel wassealed and heated to 130° C. overnight. After cooling to rt, thereaction mixture was partitioned between EtOAc (50 ml) and water (50ml). The aqueous layer was extracted with EtOAc (30 ml) and the combinedorganics were dried (Na₂SO₄) and concentrated to afford a yellow oilthat was chromatographed on a 12 g silica gel cartridge, eluting with a0-100% ethyl acetate in hexanes gradient. The pure fractions wereconcentrated to afford tert-butyl3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate(12 mg, 0.028 mmol, 48.3% yield) as a yellow solid. LCMS m/z 427.3(M+H)⁺; HPLC t_(R) 0.75 min (analytical HPLC Method A).

Step 5

A mixture of tert-butyl3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate(35 mg, 0.082 mmol) and HCl, 4N in dioxane (0.205 mL, 0.821 mmol) in DCM(1.5 mL) was stirred at rt for 8 hr. The reaction mixture was allowed tostand at rt over the weekend in the freezer. The volatiles were removedin vacuo and the residue was dried to afford3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoicacid, HCl (36 mg, 0.080 mmol, 97% yield) as a yellow solid.

Step 6

A mixture of3-((5-carbamoyl-2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoicacid, HCl (35 mg, 0.089 mmol),(Z)-N′-hydroxy-2-morpholinoacetimidamide(17.00 mg, 0.107 mmol), BOP (59.0 mg, 0.133 mmol) and Et₃N (0.037 mL,0.267 mmol) in DMF (1 mL) was stirred at room temperature for 1.5 hr.The reaction mixture was partitioned between EtOAc (20 ml) and saturatedsodium bicarbonate solution (20 ml). The organic layer was washed withwater (2×20 ml) and brine (20 ml). After drying (Na₂SO₄) and filtrationthe organic layer was concentrated to afford(Z)-4-((3-((((1-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide(40 mg, 0.070 mmol, 79% yield) as a light yellow oil. Used as is in thenext step.). LCMS m/z 512.4 (M+H)⁺; HPLC t_(R) 0.51 min (analytical HPLCMethod A).

Step 7

A mixture of (Z)-4-((3-((((1-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)-6-(cyclopropanecarboxamido)nicotinamide(40 mg, 0.070 mmol) and TBAF, 1M in THE (0.106 mL, 0.106 mmol) inacetonitrile (1 mL) was stirred at rt overnight. After stirringovernight, the reaction is complete. The reaction mixture wasconcentrated to an oil then redissolved in 1.5 mL DMF, filtered andsubmitted for purification. The reaction afforded6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)nicotinamide(12.4 mg, 0.024 mmol, 34.6% yield) LCMS m/z 494.4 (M+H)⁺; HPLC t_(R)0.53 min (analytical HPLC Method A). ¹H NMR (500 MHz, DMSO-d₆) δ 11.05(s, 2H), 10.80 (s, 1H), 8.64 (s, 1H), 8.21 (br. s., 1H), 8.04 (s, 1H),7.76 (d, J=8.1 Hz, 2H), 7.55 (br. s, 1H), 7.40 (t, J=7.9 Hz, 1H), 3.77(s, 3H), 3.19-3.13 (m, 2H), 2.02-1.95 (m, 1H), 1.57 (br. s., 2H),1.36-1.27 (m, 2H), 0.93 (t, J=7.4 Hz, 3H), 0.79 (d, J=6.1 Hz, 4H)

The Examples in Table 12 were prepared using a similar procedure used toprepare Example 576.

TABLE 12 Obs. Ex. MS QC No. Structure MW Ion RT Method 577

570.6 571.2 1.26 QC- ACN- AA-XB 578

552.6 553.0 1.37 QC- ACN- AA-XB

Example 579N-(4-((2-methoxy-3-(3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide

Step 1

To a solution of 4-bromopyridin-2-amine (300 mg, 1.734 mmol) andtriethylamine (0.725 mL, 5.20 mmol) in DCM (15 mL) at 0° C. in an icebath was added dropwise cyclopropanecarbonyl chloride (0.189 mL, 2.081mmol). This solution was allowed to warm to room temperature afteraddition was complete. After 1 hour, the reaction is complete. Quenchedwith saturated aq. sodium bicarbonate, then extracted 3×50 mL DCM. Driedover sodium sulfate, then filtered and concentrated. The reactionafforded N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (401 mg, 1.580mmol, 91% yield) as a crystalline off-white solid. Carried on directlyto the next step as-is. HPLC t_(R) 0.87 min (analytical HPLC Method A).

Step 2

A mixture of N-(4-bromopyridin-2-yl)cyclopropanecarboxamide (100 mg,0.415 mmol), Xantphos (48.0 mg, 0.083 mmol), and tert-butyl3-amino-2-methoxybenzoate (185 mg, 0.830 mmol) in dioxane (3.5 mL) wasdegassed by bubbling N2 through it for 5 minutes. Then Cs₂CO₃ (541 mg,1.659 mmol) and Pd₂(dba)₃ (38.0 mg, 0.041 mmol) were added, the vesselwas sealed, and the reaction was stirred at 130° C. for 45 minutes. Thereaction was complete by LC-MS. The reaction was cooled to roomtemperature, and then concentrated, then diluted with DCM and loadeddirectly onto a 40 g silica gel column. Eluted with 0-15% MeOH in DCM.The reaction afforded tert-butyl3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate(100 mg, 0.248 mmol, 59.7% yield).) LCMS m/z 384.2 (M+H)⁺; HPLC t_(R)0.77 min (analytical HPLC Method A).

Step 3

A mixture of tert-butyl3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoate(108 mg, 0.282 mmol) and HCl, 4N in dioxane (0.704 mL, 2.82 mmol) in DCM(3 mL) was stirred at rt for 8 hr. The reaction mixture was allowed tostir at rt. The volatiles were removed in vacuo and the residue wasdried to afford3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoicacid, HCl (100 mg, 0.261 mmol, 93% yield) as a yellow solid.) LCMS m/z328.2 (M+H)⁺; HPLC t_(R) 0.55 min (analytical HPLC Method A).

Step 4

A mixture of3-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-2-methoxybenzoicacid, HCl (40 mg, 0.114 mmol),(Z)-N′-hydroxy-2-morpholinoacetimidamide(21.81 mg, 0.137 mmol), BOP (76 mg, 0.171 mmol) and Et₃N (0.048 mL,0.343 mmol) in DMF (1 mL) was stirred at rt for 1.5 hr. The reactionmixture was partitioned between EtOAc (20 ml) and saturated sodiumbicarbonate solution (20 ml). The organic layer was washed with water(2×20 ml) and brine (20 ml). After drying (Na₂SO₄) and filtration theorganic layer was concentrated to afford(Z)-N-(4-((3-((((1-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide(44 mg, 0.094 mmol, 82% yield) as a light yellow oil. Used as is.) LCMSm/z 469.2 (M+H)⁺; HPLC t_(R) 0.50 min (analytical HPLC Method A).

Step 5

A mixture of (Z)-N-(4-((3-((((1-amino-2-morpholinoethylidene)amino)oxy)carbonyl)-2-methoxyphenyl)amino)pyridin-2-yl)cyclopropanecarboxamide (44mg, 0.094 mmol) and TBAF, 1M in THE (0.141 mL, 0.141 mmol) inAcetonitrile (1 mL) was stirred at rt over the weekend. The reaction wasincomplete, so another 300 uL of the TBAF solution was added, and thereaction allowed to stir another night at room temperature. the reactionis now complete by LC-MS. The reaction mixture was partitioned betweenEtOAc (30 ml) and brine. After drying (Na₂SO₄) and filtration theorganic layer was concentrated to afford a yellow oil. This wasdissolved in 2 mL methanol, then filtered and submitted forpurification. The reaction affordedN-(4-((2-methoxy-3-(3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)phenyl)amino)pyridin-2-yl)cyclopropanecarboxamide(22.2 mg, 0.049 mmol, 51.9% yield).) LCMS m/z 451.2 (M+H)⁺; HPLC t_(R)0.51 min (analytical HPLC Method A). ¹H NMR (500 MHz, DMSO-d₆) δ10.66-10.37 (m, 1H), 8.63 (s, 1H), 7.95 (br d, J=5.4 Hz, 1H), 7.78-7.74(m, 2H), 7.63 (br d, J=7.7 Hz, 1H), 7.34 (t, J=7.9 Hz, 1H), 6.60 (br d,J=4.4 Hz, 1H), 3.76 (s, 2H), 3.71 (s, 3H), 3.63-3.60 (m, 2H), 3.19-3.14(m, 2H), 2.60-2.53 (m, 4H), 2.00-1.95 (m, 1H), 1.57 (br s, 2H),1.35-1.28 (m, 2H)

The Examples in Table 13 were prepared using a similar procedure used toprepare Example 579.

TABLE 13 Obs. Ex. MS QC No. Structure MW Ion RT Method 580

491.6 492.3 1.26 QC- ACN- AA-XB 581

527.6 528.2 1.32 QC- ACN- AA-XB

Biological Assays

The following assay is used to show the activity for compounds of theinvention.

IFNα-Induced STAT Phosphorylation in Human Whole Blood

After an hour long incubation with compound, human whole blood (drawnwith either EDTA or ACD-A as anti-coagulant) was stimulated with 1000U/mL recombinant human IFNα A/D (R&D Systems 11200-2) for 15 min. Thestimulation was stopped by adding Fix/Lyse buffer (BD 558049). Cellswere stained with a CD3 FITC antibody (BD 555916), washed, andpermeabilized on ice using Perm III buffer (BD 558050). Cells were thenstained with an Alexa-Fluor 647 pSTAT5 (pY694) antibody (BD 612599) for30 min prior to analysis on the FACS Canto II. The amount of pSTAT5expression was quantitated by median fluorescence intensity after gatingon the CD3 positive population.

IFNα-Induced STAT Phosphorylation in Human Whole Blood Inhibition DataND—no data available

TABLE 14 Human WB IFNα-Induced Ex. No. Stat Phosph. (IC₅₀, μM) 1 2.80 20.65 3 0.98 4 0.66 5 3.30 6 0.11 7 0.024 8 0.021 9 0.016 10 0.004 110.021 12 0.011 13 0.024 14 0.05 15 0.03 16 0.56 17 0.49 18 ND 19 0.25 201.50 21 0.022 22 ND 23 0.06 24 0.24 25 0.43 26 3.90 27 2.01 28 0.21 290.13 30 1.38 31 0.38 32 0.08 33 ND 34 1.01 35 0.12 36 0.03 37 0.018 380.03 39 0.023 40 0.012 41 0.06 42 0.23 43 0.17 44 0.009 45 0.16 46 0.1447 0.14 48 0.025 49 0.05 50 0.07 51 0.16 52 0.09 53 0.21 54 ND 55 0.0456 0.12 57 0.009 58 0.011 59 0.013 60 0.023 61 0.06 62 0.08 63 0.03 640.11 65 0.016 66 0.03 67 0.06 68 0.023 69 0.03 70 0.014 71 0.025 72 0.0873 0.28 74 0.17 75 0.03 76 0.03 77 0.04 78 0.07 79 0.16 80 0.11 81 0.1882 0.07 83 0.11 84 0.13 85 0.24 86 0.30 87 0.46 88 0.23 89 0.03 90 0.0691 0.05 92 0.03 93 0.05 94 0.011 95 0.021 96 0.015 97 0.03 98 0.023 990.04 100 0.06 105 1.83 107 0.82 109 >10.00 115 3.49 116 4.97 118 3.80119 >10.00 120 0.15 121 >10.00 122 >10.00 123 >10.00 124 0.21 125 0.06126 0.63 127 0.26 128 0.03 129 0.26 130 0.49 131 0.74 132 0.30 133 0.10134 0.11 135 2.01 136 1.13 137 2.64 138 0.18 139 0.41 140 0.33 141 0.24142 5.31 143 0.32 144 1.00 145 0.27 146 0.21 147 1.72 148 1.82 149 1.95150 >10.00 151 1.55 152 1.31 153 >10.00 154 1.11 155 0.78 156 0.63157 >10.00 158 0.40 159 1.08 160 1.79 161 9.42 162 2.73 163 1.76 1640.20 165 0.53 166 ND 167 2.42 168 0.23 169 0.11 170 0.57 171 0.69 1721.44 173 0.30 174 0.56 175 0.66 176 0.45 177 1.03 178 0.55 179 0.29 1800.20 181 0.63 182 2.01 183 1.68 184 0.13 185 >10.00 186 0.79 187 1.13188 1.27 189 0.10 190 2.36 191 0.41 192 0.87 193 7.36 194 0.16 195 0.72196 1.18 197 6.20 198 1.65 199 1.08 200 0.76 201 0.29 202 1.80 203 0.46204 0.14 205 0.85 206 >10.00 207 0.48 208 1.27 209 1.37 210 0.22 2110.44 212 0.32 213 4.44 214 0.39 215 0.15 216 0.32 217 0.18 218 0.39 2195.24 220 0.20 221 0.16 222 1.48 223 0.69 224 0.88 225 0.35 226 1.16 2270.62 228 0.18 229 >10.00 230 0.51 231 1.75 232 6.51 233 0.10 234 0.30235 0.05 236 >10.00 237 0.07 238 0.08 239 0.05 240 0.18 241 0.62 2420.021 243 0.09 244 0.12 245 0.11 246 0.03 247 0.10 248 2.24 250 0.64 251ND 252 3.27 253 0.30 254 5.43 255 0.62 256 0.13 257 0.23 258 0.13259 >10.00 260 0.54 261 0.68 262 2.69 263 0.83 264 1.55 265 0.53 2662.53 267 0.15 268 0.10 269 0.04 270 0.10 271 0.09 272 0.16 273 0.07 2740.05 275 0.15 276 0.69 277 0.24 278 ND 279 0.47 280 ND 281 >10.00 2820.18 283 0.36 284 >10.00 285 ND 286 ND 287 1.26 288 0.09 289 0.15 2900.10 291 0.11 292 0.16 293 0.03 294 0.07 295 0.06 296 >10.00 297 0.03298 >10.00 299 0.014 300 0.33 301 0.03 302 0.11 303 0.10 304 0.13 3050.22 306 0.44 307 0.03 309 >10.00 310 >10.00 311 0.20 312 0.07 313 0.07314 0.26 315 0.022 316 0.33 317 0.03 318 0.08 319 0.03 320 0.05 321 0.03322 0.08 324 0.06 325 0.11 326 0.03 327 0.15 328 0.16 329 0.05 330 0.07331 0.56 332 0.04 334 0.05 335 0.05 336 0.26 337 0.07 338 0.42 339 0.04340 0.10 341 0.11 342 0.08 343 0.022 344 0.03 345 0.18 346 0.09 3470.013 348 ND 349 0.07 350 0.04 351 0.06 352 0.07 353 0.17 354 0.08 3550.38 356 0.08 357 0.88 358 0.21 359 0.34 360 0.27 361 0.19 362 0.27 3630.24 364 0.44 365 0.32 366 0.51 367 0.06 368 0.35 369 0.05 370 0.16 3710.31 372 0.15 377 1.41 379 0.56 380 ND 381 0.13 382 0.10 383 0.03 3840.04 385 0.18 386 0.49 387 0.27 388 >10.00 389 0.57 390 0.24 391 0.82392 0.023 393 0.18 394 0.42 395 0.08 396 0.12 397 0.04 398 ND 399 0.18400 0.03 401 0.18 402 0.04 403 0.19 404 0.11 405 0.09 406 0.18 407 0.16408 0.11 409 >10.00 410 0.26 411 1.80 412 4.62 413 0.17 414 0.31 4150.04 416 0.46 418 0.13 419 0.20 420 0.22 421 0.29 422 0.59 423 ND 4240.20 425 0.67 426 0.03 427 0.09 428 2.63 429 0.19 430 >10.00 431 >10.00432 0.30 433 0.16 434 0.16 435 0.26 436 0.30 437 2.41 438 2.89 439 0.44440 1.16 441 0.29 442 0.08 443 0.27 444 2.13 445 0.15 446 0.27 447 0.16448 0.14 449 ND 450 0.20 451 0.06 452 0.15 453 0.06 454 0.19 455 0.56456 0.06 457 0.77 458 1.21 459 0.08 461 0.22 462 4.45 463 0.80 464 1.11465 0.13 466 0.42 467 0.20 468 0.27 469 0.20 470 0.34 471 1.59 472 0.29473 >10.00 474 3.56 475 2.32 476 0.06 477 1.10 478 0.15 479 0.11 4800.07 481 0.39 482 0.15 483 0.06 484 0.10 485 0.13 486 0.06 487 0.20 4880.53 489 0.29 491 0.26 492 0.15 493 0.04 494 0.25 495 0.06 496 0.25 4970.11 499 0.18 500 0.37 501 1.13 502 0.15 503 0.86 504 >10.00 505 0.18506 0.25 507 0.11 508 ND 509 0.17 510 0.46 511 0.32 512 2.56 513 >10.00514 0.87 515 0.29 516 0.17 517 0.35 518 0.15 519 0.57 520 0.77 521 2.41522 0.19 523 1.68 524 3.40 525 0.24 526 0.52 527 0.95 528 0.84 529 0.20530 0.20 531 0.06 532 0.47 533 0.53 534 0.47 535 1.50 536 0.65 537 0.70538 0.39 539 0.12 540 0.46 541 1.39 542 0.89 543 ND 544 ND 545 0.22 5460.11 547 0.40 548 0.17 549 ND 550 0.24 551 0.05 552 3.60 553 0.12 554 ND555 0.04 556 1.07 557 0.72 558 1.30 559 0.83 560 2.21 561 4.36 562 0.65563 3.12 564 >10.00 565 0.25 566 0.68 567 0.70 568 ND 569 0.59 570 0.93571 1.76 573 2.00 574 0.70 575 ND 576 0.013 577 0.019 578 4.34 581 ND

1. A compound of formula I:

wherein X is N or CH; R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R² isH, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a); R^(2a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(P)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle; R^(5a) is independently at eachoccurrence, H, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃ alkyl or(CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7 membered heterocycle substitutedwith 0-3 R^(6a); R^(6a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 2.The compound according to claim 1 of the formula

wherein X is N or CH; R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R² isH, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a); R^(2a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H or C₁₋₃ alkyl; R⁵ is C₁₋₄ alkylsubstituted with 0-1 R^(5a), C₁₋₄ alkoxy substituted with 0-1 R^(5a),(CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a —(CH₂)-5-7 memberedheterocycle; R^(5a) is independently at each occurrence, H, F, Cl, Br,OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₃ alkyl or (CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7membered heterocycle substituted with 0-3 R^(6a); R^(6a) isindependently at each occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c),—S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-2 R^(a); R⁷ is H, halogen or C₁₋₃ alkyl;R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d); R^(a) at each occurrence isindependently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f); R^(b) is H, C₁₋₆ alkylsubstituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-5-7 membered heterocycle substituted with0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(d); R^(c) is C₁₋₆alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆ cycloalkyl substitutedwith 0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(d) isindependently at each occurrence, hydrogen, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆alkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(e) isindependently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkylor (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(f) is independentlyat each occurrence, hydrogen, halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃,O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5; or a stereoisomer or pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1 of theformula

wherein X is N or CH; R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R² isH, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocyclesubstituted with 0-1 R^(2a) or a 5-12 membered heterocycle substitutedwith 0-4 R^(2a); R^(2a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H or C₁₋₃ alkyl; R⁵ is C₁₋₄ alkylor C₁₋₄ alkoxy; R^(5a) is independently at each occurrence, H, F, Cl,Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₃ alkyl or (CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7membered heterocycle substituted with 0-3 R^(6a); R^(6a) isindependently at each occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c),—S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-2 R^(a); R⁷ is H, halogen or C₁₋₃ alkyl;R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d); R^(a) at each occurrence isindependently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f); R^(b) is H, C₁₋₆ alkylsubstituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-5-7 membered heterocycle substituted with0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(d); R^(c) is C₁₋₆alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆ cycloalkyl substitutedwith 0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(d) isindependently at each occurrence, hydrogen, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆alkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(e) isindependently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkylor (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(f) is independentlyat each occurrence, hydrogen, halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃,O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5; or a stereoisomer or pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 3 of theformula

wherein X is N or CH; R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r-3)-14membered carbocycle substituted with 0-1 R^(2a) or a 5-12 memberedheterocycle substituted with 0-4 R^(2a); R^(2a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H or C₁₋₃ alkyl; R⁵ is C₁₋₄ alkylor C₁₋₄ alkoxy, R^(5a) is independently at each occurrence, H, F, Cl,Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e),—NR^(e)C(O)OR^(c), C₁₋₃ alkyl or (CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7membered heterocycle substituted with 0-3 R^(6a); R^(6a) isindependently at each occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c),—S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-2 R^(a); R⁷ is H, halogen or C₁₋₃ alkyl;R¹¹ at each occurrence is independently H, C₁₋₄ alkyl substituted with0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with 0-1 R^(f),(CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(d); R^(a) at each occurrence isindependently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-3 R^(f), C₁₋₆ haloalkyl,—(CH₂)_(r)-3-14 membered carbocycle or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f); R^(b) is H, C₁₋₆ alkylsubstituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substitutedwith 0-2 R^(d), or —(CH₂)_(r)-5-7 membered heterocycle substituted with0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(d); R^(c) is C₁₋₆alkyl substituted with 0-3 R^(f), (CH₂)_(r)—C₃₋₆ cycloalkyl substitutedwith 0-3 R^(f) or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(d) isindependently at each occurrence, hydrogen, F, Cl, Br, OCF₃, CF₃, CN,NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆alkyl or (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(e) isindependently at each occurrence, hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkylor (CH₂)_(r)-phenyl substituted with 0-3 R^(f); R^(f) is independentlyat each occurrence, hydrogen, halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃,O(C₁₋₆ alkyl) or a —(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2;r is 0, 1, 2, 3, 4 or 5; or a stereoisomer or pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 4 of theformula

wherein X is N or CH; R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r-3)-14membered carbocycle substituted with 0-1 R^(2a) or a 5-12 memberedheterocycle substituted with 0-4 R^(2a); R^(2a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁴ is Hor C₁₋₃ alkyl; R⁵ is C₁₋₄ alkyl or C₁₋₄ alkoxy, R^(5a) is independentlyat each occurrence, H, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃ alkyl or(CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7 membered heterocycle substitutedwith 0-3 R^(6a); R^(6a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 6.The compound according to claim 5 of the formula

wherein X is N or CH; R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r-3)-14membered carbocycle substituted with 0-1 R^(2a) or a 5-12 memberedheterocycle substituted with 0-4 R^(2a); R^(2a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁴ is Hor C₁₋₃ alkyl; R⁶ is a —(CH₂)-5-7 membered heterocycle substituted with0-3 R^(6a); R^(6a) is independently at each occurrence, H, OCF₃, CN,NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, CN₃₋₁₀ cycloalkyl substitutedwith 0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(d); R^(a) ateach occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 7.The compound according to claim 6 of the formula

wherein X is N or CH; R² is H, —C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r-3)-14membered carbocycle substituted with 0-1 R^(2a) or a 5-12 memberedheterocycle substituted with 0-4 R^(2a); R^(2a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁴ is Hor C₁₋₃ alkyl; R⁶ is a triazole, oxadiazole, thiazole, oxazole orpyrazole substituted with 0-3 R^(6a); R^(6a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 8.The compound according to claim 7 of the formula

wherein X is N or CH; R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl,pyridine, pyridazine, pyrazole, triazole or piperazine, all of which,except the H group, may be substituted with 0-3 R^(2a); R^(2a) isindependently at each occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),—(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),—(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,—(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),—NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(P)R^(c),—S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3 R^(a), C₁₋₆ haloalkyl,C₂₋₆ alkenyl substituted with 0-3 R^(a), —(CH₂)_(r)-3-14 memberedcarbocycle substituted with 0-1 R^(a) or a —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-2 R^(a); R⁴ is H or C₁₋₃ alkyl; R⁶ is atriazole, oxadiazole, thiazole, oxazole or pyrazole substituted with 0-3R^(6a); R^(6a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, CN₃₋₁₀ cycloalkyl substitutedwith 0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(d); R^(a) ateach occurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(P)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 9.The compound according to claim 1 of the formula

wherein R¹ is H, CD3, C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R² is H,—C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r)-3-14 membered carbocycle substitutedwith 0-1 R^(2a) or a 5-12 membered heterocycle substituted with 0-4R^(2a); R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle; R^(5a) is independently at eachoccurrence, H, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃ alkyl or(CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7 membered heterocycle substitutedwith 0-3 R^(6a); R^(6a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, CMalkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 10.The compound according to claim 9 of the formula

wherein R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, pyridine,pyridazine, pyrazole, triazole or piperazine, all of which, except the Hgroup, may be substituted with 0-3 R^(2a); R^(2a) is independently ateach occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(P)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁴ is Hor C₁₋₃ alkyl; R⁶ is a triazole, oxadiazole, thiazole, oxazole orpyrazole substituted with 0-3 R^(6a); R^(6a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(P)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 11.The compound according to claim 1 of the formula

wherein R¹ is H, CD₃, C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R² is H,—C(O)R^(2a); C₁₋₆ alkyl, —(CH₂)_(r-3)-14 membered carbocycle substitutedwith 0-1 R^(2a) or a 5-12 membered heterocycle substituted with 0-4R^(2a); R^(2a) is independently at each occurrence, H, OCF₃, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R³ is H,C₁₋₃ alkyl or C₃₋₆ cycloalkyl; R⁴ is H, C₁₋₃ alkyl or C₃₋₆ cycloalkyl;R⁵ is C₁₋₄ alkyl substituted with 0-1 R^(5a), C₁₋₄ alkoxy substitutedwith 0-1 R^(5a), (CH₂)_(r)-phenyl substituted with 0-3 R^(5a) or a—(CH₂)-5-7 membered heterocycle; R^(5a) is independently at eachoccurrence, H, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),—(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₃ alkyl or(CH₂)_(r)-phenyl; R⁶ is a —(CH₂)-5-7 membered heterocycle substitutedwith 0-3 R^(6a); R^(6a) is independently at each occurrence, H, OCF₃,CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 12.The compound according to claim 11 of the formula

wherein R² is H, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, pyridine,pyridazine, pyrazole, triazole or piperazine, all of which, except the Hgroup, may be substituted with 0-3 R^(2a); R^(2a) is independently ateach occurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁴ is Hor C₁₋₃ alkyl; R⁶ is a triazole, oxadiazole, thiazole, oxazole orpyrazole substituted with 0-3 R^(6a); R^(6a) is independently at eachoccurrence, H, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b),—(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b),CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)_(P)R^(c), C₁₋₆ alkyl substituted with 0-3R^(a), C₁₋₆ haloalkyl, C₂₋₆ alkenyl substituted with 0-3 R^(a),—(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a) or a—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-2 R^(a); R⁷ is H,halogen or C₁₋₃ alkyl; R¹¹ at each occurrence is independently H, C₁₋₄alkyl substituted with 0-3 R^(f), CF₃, C₃₋₁₀ cycloalkyl substituted with0-1 R^(f), (CH₂)_(r)-phenyl substituted with 0-3 R^(d) or —(CH₂)_(r)-5-7membered heterocycle substituted with 0-3 R^(d); R^(a) at eachoccurrence is independently H, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),—(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,—(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),—(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,—NR^(b)S(O)_(P)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-3 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle or—(CH₂)_(r)-5-7 membered heterocycle substituted with 0-3 R^(f); R^(b) isH, C₁₋₆ alkyl substituted with 0-3 R^(d), C₁₋₆ haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or —(CH₂)_(r)-5-7 memberedheterocycle substituted with 0-3 R^(f) or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(d); R^(c) is C₁₋₆ alkyl substituted with 0-3 R^(f),(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-3 R^(f) or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(d) is independently at each occurrence,hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e), —(CH₂)_(r)C(O)R^(c),—NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆ alkyl or (CH₂)_(r)-phenylsubstituted with 0-3 R^(f); R^(e) is independently at each occurrence,hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or (CH₂)_(r)-phenyl substitutedwith 0-3 R^(f); R^(f) is independently at each occurrence, hydrogen,halo, CN, NH₂, OH, C₃₋₆ cycloalkyl, CF₃, O(C₁₋₆ alkyl) or a—(CH₂)_(r)-5-7 membered heterocycle; p is 0, 1, or 2; r is 0, 1, 2, 3, 4or 5; or a stereoisomer or pharmaceutically acceptable salt thereof. 13.A compound which is6-cyclopropaneamido-4-{[2-methoxy-3-(5-{1-[(2-methoxyethyl)carbamoyl]propyl}-1,2,4-oxadiazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(2-methoxy-3-{5-[1-(morpholin-4-yl)-1-oxopentan-2-yl]-1,2,4-oxadiazol-3-yl}phenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-{[2-methoxy-3-(5-{1-[(2-methoxy ethyl)carbamoyl]butyl}-1,2,4-oxadiazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide,tert-butylN-[(1R,2R)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}propyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(1R,2R)-1-acetamido-2-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,methylN-[(1R,2R)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}-2-hydroxypropyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(1R,2R)-2-hydroxy-1-propanamidopropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,tert-butylN-[(1R)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}ethyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(1R)-2-hydroxy-1-propanamidoethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(3-{3-[(1R)-1-acetamido-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,(2R)-2-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}-2-acetamidoethylacetate,6-cyclopropaneamido-4-[(3-{3-[(1R)-2-hydroxy-1-(2-methoxyacetamido)ethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-1-acetamido-2-hydroxypropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-2-hydroxy-1-(2-methoxyacetamido)propyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,tert-butylN-[(1S,2S)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}propyl]carbamate,6-cyclopropaneamido-4-[(3-{3-[(1S,2S)-2-hydroxy-1-propanamidopropyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,tert-butylN-[(1S)-2-(tert-butoxy)-1-{5-[3-({6-cyclopropaneamido-3-[(2H3)methylcarbamoyl]pyridazin-4-yl}amino)-2-methoxyphenyl]-1,2,4-oxadiazol-3-yl}ethyl]carbamate,or6-cyclopropaneamido-4-[(3-{3-[(1S)-1-acetamido-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}-2-methoxyphenyl)amino]-N-(2H3)methylpyridazine-3-carboxamide,or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising one or more compounds according to claim 1 and apharmaceutically acceptable carrier or diluent.
 15. A method of treatinga disease, comprising administering to a patient in need of suchtreatment a therapeutically-effective amount of a compound according toclaim 1, wherein the disease is an inflammatory or autoimmune disease.16. The method of claim 15 wherein the inflammatory or autoimmunedisease is multiple sclerosis, rheumatoid arthritis, ankylosingspondylitis, inflammatory bowel disease, systemic lupus erythematosus,psoriasis, psoriatic arthritis, Crohn's Disease, Sjögren's syndrome orscleroderma.